Transcription and Translation in Health and Disease
By Manoj Garg
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About this ebook
Transcription and Translation in Health and Disease provides a detailed overview of the regulators underlying transcription and translation in relation to a variety of human diseases and disorders. Beginning with an introduction into the current perspectives relating to these processes in human disease, the book expands to focus on specific mechanisms underlying conditions such as arthritis, cancer, neurological disorders, diabetes and cardiovascular disease. This book considers RNA processing and related mechanisms in eukaryotes including RNA splicing, RNA binding proteins, RNA interference, microRNAs, RNA editing, transcription factors, RNAi screening, CRISPR activation, CRISPR-Cas9 interference, and post-translational modifications.
It provides a structured and detailed overview of the various regulators underlying molecular processes and their impact on health and disease, equipping readers with the necessary knowledge for further investigation in the areas of treatment and therapeutic intervention.
- Discusses the role played by transcription and translational regulation in various diseases, including cancer, diabetes, cardiovascular disease and neurological disease
- Considers a range of post-transcriptional regulators, including RNA-binding proteins, non-coding RNAs, epigenetic modifiers, alternative splicing and telomerase-binding proteins
- Covers the topic from fundamental knowledge to the latest developments in clinical application
- Includes a section dedicated to therapeutic applications
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Transcription and Translation in Health and Disease - Manoj Garg
Transcription and Translation in Health and Disease
First Edition
Manoj Garg
Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, India
Gautam Sethi
Department of Pharmacology; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Amit Kumar Pandey
Amity Institute of Biotechnology, Amity University Haryana, Manesar, Haryana, India
fm01-9780323995214Table of Contents
Cover image
Title page
Copyright
Contributors
About the editors
Preface
Section I: Introduction
Chapter 1: Current perspective of transcriptional regulators in human health and diseases
Abstract
Introduction
Key transcriptional regulators and their critical role in regulating the transcription
Dysregulation of transcriptional regulators in diabetes
Dysregulation of transcriptional regulators in human cancers
Misregulation of transcription factors (TFs) and mediator coactivation complex
References
Section II: Transcriptional and translational regulators in cancer
Chapter 2: Role of alternative splicing in health and diseases
Abstract
Introduction
Splicing and alternative splicing
Alternative splicing in disease
References
Chapter 3: Role of transcriptional and posttranscriptional regulation of sphingolipid genes in molecular heterogeneity of breast cancer
Abstract
Introduction to sphingolipids
Breast cancer heterogeneity
Sphingolipid gene expression in different subtypes of breast cancer
Molecular mechanisms by which sphingolipids regulate gene expression in signaling cascades
Posttranscriptional modifications
References
Chapter 4: Who dictates and when: Genetic and epigenetic dictatorships in breast cancer response and resistance to therapy
Abstract
Introduction
Breast cancer subtypes
Breast cancer treatment
Response to therapy and drug resistance
Genetic vs epigenetic dictators
References
Chapter 5: Cross-talk between NF-κB and telomerase in cancer: Implications in therapy
Abstract
Introduction
Regulation of telomerase by NF-κB in cancer
Regulation of NF-κB activity by telomerase
Implications in cancer therapy and future directions
References
Chapter 6: Genome editing and regulation of transcription and translational using CRISPR-Cas9 system
Abstract
Central dogma of molecular biology
Intervention of central dogma: Correcting errors in genetic diseases by gene editing
Gene editing by CRISPR-Cas9 system
Examples of CRISPR-Cas9-based gene editing in vitro and in vivo
Nobel Prize 2020
References
Chapter 7: Regulation of posttranscriptional events by RNA-binding proteins
Abstract
Acknowledgment
Introduction
Dysregulation of RBPs involved in posttranscriptional regulation
Nascent mRNA bound proteins in cancer
Cap-binding proteins in cancer
Splicing associated proteins in cancer
Poly(A) tail and alternative polyadenylation-dependent proteins in cancer
Modified base recognizing proteins in cancer
mRNPs involved in nuclear export and their role in cancer
mRNPs involved in subcellular localization and their role in cancer
mRNPs in translation and cancer
mRNP stability and cancer
Conclusions
References
Chapter 8: The language of posttranslational modifications and deciphering it from proteomics data
Abstract
Conflict of interest
Author contributions
Introduction
PTMs in cancer
PTM cross-talks are prevalent in health and disease
PTMs in drug resistance
PTMs and SNPs
Shotgun proteomics for studying proteins and their modifications
Data analysis for PTMs
Functional analysis of protein mod-forms
Conclusion
References
Section III: Transcriptional and translation regulators of other diseases
Chapter 9: Noncoding RNAs in human health and diseases
Abstract
Introduction
Noncoding RNA
Types of noncoding RNA
Role of noncoding RNAs in diseases
Role of ncRNAs in diabetes
Conclusion
Perspectives and future directions
References
Chapter 10: MiRNAs as epigenetic regulators for gut microbiome
Abstract
Introduction
MicroRNA discovery and biogenesis
Gene regulation by miRNAs
miRNAs in host immune system
Gut microbiome—As a regulator of wellness and diseases
Microbiota-miRNA interplay to influence gene expression
Epithelial cell microRNAs in gut immunity
Gut microbiome—miRNA And human diseases
Concluding comments and future viewpoints
References
Chapter 11: Crosstalk between microRNAs and epigenetics during brain development and neurological diseases
Abstract
Acknowledgments
Introduction
Epigenetic changes
Neural development and miRNAs
Neural development and epigenetics
Neurodevelopmental disorders
Neurodegenerative diseases
Conclusion
References
Chapter 12: Implications of miRNA in autoimmune and inflammatory skin diseases
Abstract
Introduction
Structure of the human skin
Micro-RNAs and its biogenesis
miRNA and skin diseases
Emerging miRNA-based drugs
References
Chapter 13: Micro-RNA contribution to angiogenesis in cancer
Abstract
Introduction
miRNA-190
miRNA-29b
miRNA-6086
miRNA-378a-5p
miRNA-221-3p
Conclusion
References
Chapter 14: Emerging role of mRNA and RNA binding proteins in Diabetes
Abstract
Introduction
RNA binding proteins
RBPs at the crossroad of diabetes mellitus
Posttranscriptional modifications in diabetes
RNA-based therapeutics for diabetes
Conclusion
References
Chapter 15: Caenorhabditis elegans: An interesting host for aging-related studies
Abstract
Acknowledgment
An overview of the oxidative stress theory of aging
Oxidative stress and age-associated diseases
The beneficial properties of the CE-based model for in vitro studies
Natural products used in the CE model for aging-related studies
CE model used in antioxidant study
CE model in the antiaging study
Limitations of the CE-based model
Conclusion and future directions
References
Chapter 16: The role of LncRNA and micro-RNA targeting GLI transcription factors in human cancers
Abstract
Overview of GLI proteins
GLI as a nuclear executor of the hedgehog (Hh) signaling pathway
Long noncoding RNA as a potential regulator of GLI activity
miRNA as a potential regulator of GLI activity
References
Section IV: Therapeutics
Chapter 17: Inhibitors targeting epigenetic modifications in cancer
Abstract
Conflict of interests
Introduction
Mechanism of epigenetic regulation
Epigenetic regulation in cancer
Epigenetic diagnostic biomarkers in various cancers
Epigenetic targets for cancer treatment
Conclusion
Glossary
References
Chapter 18: Modulation of epigenetic methylation enzymes by synthetic and natural agents
Abstract
Introduction
DNA methylation in cancer
Histone lysine methylation in cancer
PR domain-containing genes with zinc fingers (PRDMs)
Mixed lineage leukemia
Nuclear receptor binding Su (var)3–9, enhancer of zeste, and trithorax domain protein 1
Enhancer of Zeste 2 homolog Polycomb repressive complex
SET and MYND domain proteins
Role of histone lysine demethylases in cancer
Lysine-specific histone demethylase 1
JmjC domain-containing demethylase GASC1 (JMJD2C)
Jumonji, AT-rich interactive domain demethylase Plu-1 (JARID1B)
Retinoblastoma binding protein 2 (RBP2)
Histone arginine methyltransferases
Histone lysine methylase and demethylase inhibitors in cancer
Natural products and their semisynthetic derivatives as the inhibitors of epigenetic enzymes (methylase and demethylase)
Conclusion and future perspectives
References
Chapter 19: Transcriptional regulatory network associated with multiple sclerosis pathogenesis
Abstract
Introduction
Conclusion
References
Chapter 20: Role of adipokines in the pathophysiology of coronary artery disease
Abstract
Conflict of interest
Introduction
Risk factors for coronary artery disease
Role of Adipokines in the development of CAD
Role of glucocorticoids in coronary artery disease
References
Index
Copyright
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Contributors
Khurram Aamir
School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia
Akhtar Saeed College of Pharmacy, Canal Campus, Lahore, Pakistan
Suhailah Abdullah Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Yogita K. Adlakha
Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, Faridabad, Haryana
Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, India
Suruchi Aggarwal Computational and Mathematical Biology Centre (CMBC), Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
Aditya Arya School of Biosciences, Faculty of Science, University of Melbourne, Parkville, VIC, Australia
Vinit Singh Baghel Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
Prashant Bhatt State Forensic Science Laboratory, Sagar, Madhya Pradesh, India
Megan Butler Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX, United States
Yi Ying Cheok Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Ujjaini Dasgupta Laboratory of Sphingolipid Biology, Amity Institute of Integrative Sciences and Health, Amity University Haryana, Manesar, Haryana, India
Uma Dhawan Department of Biomedical Science, Bhaskaracharya College of Applied Sciences, University of Delhi, Dwarka, New Delhi, India
Vineeta Dixit Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
Manoj Garg Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, India
Payal Gupta Computational and Mathematical Biology Centre (CMBC), Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
Shafaque Imran Department of Cardiac Biochemistry, AIIMS, New Delhi, India
Kailash Prasad Jaiswal Department of Cardiac Biochemistry, AIIMS, New Delhi, India
Ekta Khattar Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be) University, Mumbai, Maharashtra, India
Anuradha Kirtonia Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, India
Alan Prem Kumar
Department of Pharmacology
NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Sandeep Kumar Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, United States
Santosh Kumar Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India
Rachana Kumari Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, India
Reena Kumari Department of Physiology, Augusta University, Augusta, GA, United States
Chung Yeng Looi School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia
Shrey Madeka Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be) University, Mumbai, Maharashtra, India
Priya Madhavan School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia
Chakrabhavi Dhananjaya Mohan Department of Studies in Molecular Biology, University of Mysore, Mysore, Karnataka, India
Chandan Seth Nanda
The Francis Crick Institute
Pear Bio, London, United Kingdom
Amit Kumar Pandey Amity Institute of Biotechnology, Amity University Haryana, Manesar, Haryana, India
Gouri Pandya Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, India
Trishna Pani Laboratory of Sphingolipid Biology, Amity Institute of Integrative Sciences and Health, Amity University Haryana, Manesar, Haryana, India
Kanchugarakoppal S. Rangappa Institution of Excellence, Vijnana Bhavan, University of Mysore, Mysore, Karnataka, India
Vibha Rani Transcriptome Laboratory, Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
Saurabh Saxena Next Gen Invitro Diagnostics Pvt Ltd, Gurugram, Haryana, India
Gautam Sethi
Department of Pharmacology
NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Muthu K. Shanmugam Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Harsh Sharma Amity Institute of Integrative Science and Health, Amity University Haryana, Manesar, Haryana, India
Ravi Datta Sharma Amity Institute of Integrative Science and Health, Amity University Haryana, Manesar, Haryana, India
Sapnita Shinde Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
Dhananjay Shukla Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
Aishwarya Singh Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, India
Shivani Singhal Transcriptome Laboratory, Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
Vibha Sinha Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
Rohit Srivastava Laboratory of Medical Transcriptomics, Department of Endocrinology, Nephrology Services, Hadassah Hebrew-University Medical Center, Jerusalem, Israel
Sanjay K. Srivastava Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX, United States
Swayam Prakash Srivastava
Department of Pediatrics
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, United States
Vaisnevee Sugumar School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia
Shalini Swaroop Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, Faridabad, Haryana, India
Manoj Kumar Tembhre Department of Cardiac Biochemistry, AIIMS, New Delhi, India
Atul Kumar Tiwari Department of Zoology, Dr. Bhanvar Singh Porte Govt. College, Pendra, Chhattisgarh, India
Pratima Tripathi Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh, India
Nandini Verma
TNBC Precision Medicine Research Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Tata Memorial Center, Navi Mumbai
Homi Bhabha National Institute, Training School Complex, Mumbai, Maharashtra, India
Shantini Vijayabalan School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia
Naveen Kumar Vishvakarma Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
Sagar Vyavahare Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, United States
Won Feng Wong Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Amit Kumar Yadav Computational and Mathematical Biology Centre (CMBC), Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
Kusum Yadav Amity Institute of Integrative Science and Health, Amity University Haryana, Manesar, Haryana, India
Carson Zabel Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX, United States
About the editors
Dr. Gautam Sethi is a tenured Associate Professor in the Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. The focus of his research has been to elucidate the mechanism(s) of activation of oncogenic transcription factors by carcinogens and inflammatory agents and the identification of novel inhibitors of these proteins for prevention of and therapy for cancer.
Dr. Manoj Garg is Professor and Assistant Director at the Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Uttar Pradesh, Noida, India. Dr. Garg is Fellow of the Royal Society of Biology (FRSB), United Kingdom, and has 18 years of research experience in human malignancies. Dr. Garg was awarded the DBT—Ramalingaswami Fellowship, SERB—Early Career Research Award, and ICMR—Shakuntala Amir Chand Prize for his research contributions. Dr. Garg has extensive research experience and expertise from the National Institute of Immunology, New Delhi, India, Cancer Science Institute, National University of Singapore, Singapore, and the University of California, Los Angles, United States in cutting-edge research areas including genome engineering, genomics, transcriptomics, noncoding RNA, shRNA, biomarker, and drug discovery in different subtypes of acute myeloid leukemia, pancreatic carcinoma, esophageal squamous cell carcinoma, thyroid carcinoma, and liposarcoma.
Dr. Amit Kumar Pandey is Assistant Professor at the Amity Institute of Biotechnology, Amity University Haryana, Haryana, India. He completed his postdoctoral training at the Cancer Science Institute of Singapore, National University of Singapore, Singapore, where he worked on exploring the role of miRNAs in epigenetic regulation of metastatic breast cancer, and Max Delbruck Center for Molecular Medicine, Berlin, Germany, where he worked on exploring the role of noncoding RNAs in metabolism. Dr. Pandey has been working in the field of noncoding RNAs for the past 12 years. He has worked extensively in molecular and cell biology, cell signaling, and next-generation sequencing.
Preface
The knowledge revolving around genomics, transcriptomic, and proteomic has proven essential in interpreting the functional aspects of the different coding and noncoding elements present in the eukaryote genome, revealing the molecular mechanisms contributing to human health and disease. In the present era, transcriptional and posttranscriptional regulation in conjunction with translational regulation in health and disease is one of the fascinating areas of research, discussion, and drug development. This book combines the basic and modern knowledge of transcriptional and translational gene regulation to address the complex problems. The book pays attention to RNA processing, splicing, RNA-binding proteins, ribosomal RNA, microRNAs, long noncoding RNA and their biogenesis, and RNA interference, modifications, and other key mechanisms in regulating the eukaryotic genome. Also, the book touches on the basic yet vital matters of transcription factors, chromatin remodelers, and enhancers that play an important role in the process of transcription regulation along with advanced technologies such as RNA editing, RNAi screening, and CRISPR-Cas9 interference in succeeding chapters post introduction. A continued study on translational and posttranslational regulators broadens the subject matter and enlightens the readers about the critical role of RNA processing in various diseases such as cancer, diabetes, and other diseases. Our objective is to provide the readers with a comprehensive overview of transcription, translation, and their regulation in human health and diseases.
We thank all the authors and all coauthors who have immensely contributed to various chapters in the book and made it possible to bring the vast knowledge of gene expression regulation under a single canopy.
Manoj Garg
Gautam Sethi
Amit Kumar Pandey
Section I
Introduction
Chapter 1: Current perspective of transcriptional regulators in human health and diseases
Aishwarya Singha; Rachana Kumaria; Anuradha Kirtoniaa; Gouri Pandyaa; Amit Kumar Pandeyb; Manoj Garga a Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, India
b Amity Institute of Biotechnology, Amity University Haryana, Manesar, Haryana, India
Abstract
Transcription is a highly complex and most critical step associated with the expression of the genes by utilizing the information present in the deoxyribonucleic acid (DNA) to generate messenger ribonucleic acid (RNA). The process of transcription is influenced by a variety of regulators and is known as transcriptional regulators. Transcriptional regulations are central in controlling the gene expression and key biological processes which allow the cellular machinery to respond to a variety of intracellular and extracellular signals to decide cell identity and cellular activity. The transcriptional regulators include chromatin modifiers, DNA methylation, N6-methyladenosine (m6A), noncoding RNA, alternative splicing, transcription factors, enhancers, etc. In the present chapter, we have discussed the recent advancements and the mechanistic role of these transcriptional regulators in controlling gene expression. Additionally, we have highlighted and provided an overview that how deregulation of transcriptional regulators either due to genetic mutations or altered expression leads to the development and progression of human diseases with a special focus on human cancers.
Keywords
Transcription; Regulator; Noncoding RNA; DNA methylation; N6-methyadenosine
Introduction
Transcription is a complex process where the information present in a strand of deoxyribonucleic acid (DNA) is generated into ribonucleic acid (RNA) with the help of RNA polymerases, and transcription factors (TFs) [1]. TFs can recognize specific DNA sequences known as enhancer and promoter sequences and recruit RNA polymerase to the transcription site and form the transcription initiation complex. During the transcription, RNA polymerase incorporates complementary bases to the DNA strand to generate an mRNA molecule which acts as a blueprint for protein synthesis (Fig. 1). The main concepts of transcriptional regulation were started approximately six decades back in bacterial systems with the landmark work of François Jacob and Jacques Monod [1,2]. Later on, several groups demonstrated that TFs can bind at the specific site of DNA which lead to the recruitment of the transcription assembly [3,4]. Now, transcription is considered to be the very first step in the process of gene expression and is responsible for the development and maintenance of specific cell types in a spatiotemporal manner [3,4]. The entire transcription process is completed in three major steps, namely, initiation, elongation, and termination. Eukaryotic transcription works out similarly to the prokaryotes in terms of the basic steps but with increased complexity. A few major differences between the two include: initiation being more complex, termination not involving any stem-loop structures, involvement of three enzymes viz. RNA polymerases I, II, III, and the chromatin and transcriptional regulation are more extensive in comparison to prokaryotes [5–7]. During the past two decades, there was a huge advancement in the field of molecular biology, biochemistry, and chemistry which resulted in the development of several key technologies for understanding the human genome and their associated processes including transcription and translational regulation. The emerging pieces of evidence have revealed that there are large number of transcriptional regulators like chromatin modifiers, DNA methyl-transferases, N6-methyladenosine (m6A), noncoding RNAs (ncRNAs), alternative splicing, TFs, and enhancers, etc. Also, the emerging research has enhanced our knowledge about the control of cellular gene expression programs and how the dysregulated gene expression led to different human diseases including cancer, cardiovascular, diabetes, autoimmunity, and neurological disorders. Gene expression can be dysregulated either due to mutations or altered expression of TFs, chromatin regulators, regulatory elements, cofactors, and ncRNAs. In the present chapter, we have discussed the mechanisms of transcription regulators and their potential role in transcription to modulate gene expression. Also, the dysregulation of the transcriptional regulators in the development of the diseases has been discussed, especially in the human malignancies.
Fig. 1Fig. 1 Schematic representation of the central dogma of molecular biology. An overview of the processes associated with the flow of genetic information from deoxyribonucleic acid (DNA) to ribonucleic acid (RNA) through RNA polymerases, a process known as transcription. These RNA sequences are translated into proteins through ribosomes, a process known as translation. Recently, few anomalies to central dogma have been noticed. For instance, a large portion of the DNA does not translate into protein but is transcribed into a variety of functional RNAs known as noncoding RNAs.
Key transcriptional regulators and their critical role in regulating the transcription
There are several crucial transcriptional regulators to maintain cellular homeostasis which include chromatin modifiers, DNA methylation, N6-methyladenosine (m6A), ncRNAs, alternative splicing, TFs, and enhancers, etc.
Chromatin modifiers
Chromatin structure is one of the important regulators of various aspects of transcription which are mainly mediated via RNA polymerase II. The structure of the chromatin is regulated by several mechanisms like modification of histones, eviction of histones, the addition of histone variant, and chromatin remodeling [8–11].
Histone modifications
Approximately 147 bp long stretch of DNA is tightly wrapped around the histone in the nucleus of the eukaryotes to form a nucleosome [10,12]. Histone octamers consist of two copies of core proteins; H2A, H2B, H3, and H4. Histone modifications are key processes in controlling the transcription and gene expression by regulating the accessibility of RNA polymerases and their cofactors (Fig. 2) [8,13]. Rearrangement of the histones takes place through a variety of posttranslational modifications at the histone tails and globular domains. A large number of enzymes including histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone methyltransferases (HMTs) are responsible for posttranslational modifications either through the addition or removal of methyl groups, acetyl groups [14,15] (Fig. 2). Apart from these modifications, ubiquitination, phosphorylation at serine and threonine residues, ADP-ribosylation, and sumoylation at lysine (K) has been observed to be crucial for gene expression [9,16]. Histone modifications can either enhance the chromatin condensation to sequester promoter elements or increase the spacing between histones to allow the association of TFs and polymerase on specific DNA sequences [11,16]. For example, acetylation of H3 and H4, and di- or trimethylation of H3K4, is known to enhance transcription leading to increased gene expression and such modifications are known as euchromatin modifications. On the other hand, H3K27 and H3K9 trimethylation by the polycomb complex PRC2 are known to suppress transcription through chromosomal compaction leading to gene silencing and such modifications are named heterochromatin modifications [17]. These modifications are scattered in specific patterns in the core promoter, upstream region, and the 5′ and 3′ end of the ORF (Fig. 1). Importantly, the location of a modification has a great influence on the transcription and expression of genes [18].
Fig. 2Fig. 2 Illustration of transcriptional regulations through histone modifications. The epigenetic modifications like methylation and acetylation on lysine and arginine residues of histones can efficiently change the chromatin architecture through chromatin remodeling. The methylated histones lead to condensation of the chromatin (heterochromatin) to repress the transcription of the DNA. The acetylated histones caused the opening of the chromatin (euchromatin) to activate the transcription of genes.
DNA methylation
DNA methylation is now a well-recognized epigenetic process where the addition of methyl groups at cytosine (C) residues changes the structure of chromatin which further modulates the transcriptional activity [18,19]. Now, there are enough experimental pieces of evidence and observations that more than 90% of methyl-C are localized in the dinucleotide (CpG), where p
denotes phosphodiester bond [20]. Approximately 28 million CpG dinucleotides are present in the human genome and around 70% to 80% of CpG cytosines are methylated [21,22]. Transcription regulation at promoters is mainly regulated through methylation of cytosine residues within CpG dinucleotides where the methyl group is added to the 5′ end of the cytidine and is also called 5-methylcytosine (5mC/m⁵C) [22]. Methylation at CpG islands specifically within the promoter of a gene can silence gene expression through transcriptional repression. The process of DNA methylation is catalyzed by DNA methyltransferases (DNMT). In eukaryotes, DNMT1, DNMT3 alpha (DNMT3A), and DNMT3 beta (DNMT3B) are the major enzymes for DNA methylation [20,23]. The DNMT1 is also known as maintenance
methyltransferase because of its ability to maintain the methylation pattern of the parental DNA strand (Fig. 3). DNMT1 is highly expressed and has ∼ 100-fold activity in regards to hemimethylated DNA than other DNMTs. DNMT3a and DNMT3b can act on both unmethylated and hemimethylated DNA [19,23,24]. The inactivation of either DNMT3A or DNMT3B in the murine model has shown that DNA methylation is crucial for developmental fates. Several studies have shown that methyl binding domain (MBD) proteins, the SET and RING finger domain associated (SRA) proteins, and methyl-CpG-binding zinc finger proteins can bind to methyl-CpG in DNA [20,25]. The interaction of methyl-CpG binding protein 2 (MeCP2) with methylated CpG islands resulted in heterochromatin to repression of the transcriptional process [25]. The potential role of MeCP2 in modulating the chromatin structure and transcription is well documented in MeCP2 mutated Rett syndrome (X-linked dominant inheritance) [26].
Fig. 3 Schematic of DNA methylation. DNA methylation is an epigenetic modification that involves the transfer of methyl group (CH3) to the C5 position of the cytosine with the help of DNA methyltransferase (DNMT) and takes place at cytosine residue followed by guanine (CpG).
N6-methyladenosine (m6A)
The m6A is an important and most abundant posttranscriptional mRNA modification in eukaryotes [27]. The m6A regulates several important biological processes through methyltransferases, demethylases, and effector proteins that recognize m6A modification [28,29]. The m6A modification on transcripts regulates a variety of fundamental molecular and cellular functions including pre-mRNA, microRNA biogenesis, splicing, nuclear transport, and translation [30]. This modification is present in rRNA, tRNA, small nuclear RNA (snRNA), and lncRNA. Identification of proteins associated with m6A regulation was the most significant breakthrough in this field and establish the roles of m6A as readers
(effectors which recognize m6A) writers
(m6A methyltransferases), and erasers
(m6A demethyltransferases) [30,31]. METTL3 (methyltransferase like-3) was discovered as the first writer that helped in loading the m6A on RNA [30,31]. Also, METTL14, Wilms’ tumor 1 associated protein (WTAP), KIAA1429, and METTL5 are key components of the m6A methyltransferase complex [32]. Silencing of METTL3/METTL14 decreased the ratio of m6A/A. On the other hand, the silencing of WTAP inhibited the METTL3 complex binding to RNA. This indicates that WTAP can recruit the RNAs. Fat mass and obesity-associated and ALKB homolog 5 (m6A demethylase) proteins were recognized as the first eraser
enzyme which overrides RNA modification to cellular homeostasis. The reader
proteins are known to have direct interaction with m6A via the YTH domain. YTHDF, YTH domain family proteins 1 and 3 enhance translation of m6A-modified mRNA. YTHDF2 promotes RNA degradation [33,34].
Noncoding RNAs
Initially, ncRNAs were considered transcriptional noise
in the human genome [35–38]. The advancement in the high throughput sequencing has provided a better understanding of the complexity of the human genome and shown that there are a huge number of genes that are either transcribed and code for proteins or transcribed but unable to code a functional protein known as ncRNAs [35,37–40]. The human genome consists of approximately 20,000 protein-coding genes and a variety of ncRNAs which are many folds higher compared to protein-coding genes [36–38]. Although the functions of the majority of ncRNAs are still unknown, several studies displayed that ncRNAs play a vital role in regulating the gene expression either through transcriptional or posttranscriptional modifications [35,41]. The noncoding part of the genome is well transcribed and known to generate thousands of small (< 200 nucleotides; miRNAs, siRNAs, snRNAs, and piRNAs) and long ncRNAs (> 200 nucleotides). Out of these miRNAs, siRNAs, and lncRNAs stand to be one of the most widely studied classes of ncRNAs and are known to control the expression of genes at transcriptional and posttranscriptional levels [42,43]. During the past decade, the majority of ncRNAs have been found to recruit chromatin regulators at the specific site of DNA to modulate gene expression (Fig. 4) [39,42–44]. The miRNAs are known to act as sponges where they bind to a specific target messenger RNA to block the translation (Fig. 4). Recent studies have displayed that ncRNAs can control posttranscriptional processing of mRNAs such as capping, splicing, editing, translation, transportation, stability, and degradation [45]. For instance, nuclear localization of MALAT1 lncRNA can affect alternate splicing through phosphorylation of serine and arginine-rich splicing factors [46]. The Gomafu/MIAT lncRNA has neuron-specific expression, blocks spliceosome formation, and affects mRNA splicing through sequestering of splicing factor 1 [47].
Fig. 4 Illustration of transcriptional and translational regulation through long noncoding RNAs. LncRNAs can modify through different mechanisms as (A) recruitment of chromatin-modifying enzymes to the target gene, leading to activation or repression of transcription (B) recruitment of transcription factors adjacent to the target gene locus to promote transcription (C) acting as a scaffold for various proteins (D) through sponging the microRNAs (E) through modification of splicing processes.
Alternative splicing
The current genomic era focuses on the global gene descriptions and transcript structure in the human genome. The evolution of high-throughput RNA sequencing approaches and bioinformatic analysis methods have uncovered the role of alternative splicing in regulating the transcription processes which in turn regulate key cellular processes such as development, cell growth, differentiation, cellular lineages, and cell death [48–51]. Alternative splicing is a crucial mechanism for gene regulation and expression that allows the generation of more than one unique mRNA species from a single gene thereby leading to the generation of a vast diversity of proteins from a limited number of genes [48–51]. Hence, the process of alternative splicing stands to be a ubiquitous regulatory mechanism that includes exon skipping or removal, usage of alternative 3′ and 5′ splice sites, and intron retention. During the splicing, an RNA-protein complex named the spliceosome
attaches itself to the primary mRNA containing both introns and exons. Spliceosomes are crucial for bringing all exons together while removing the introns to generate a functional protein. Spliceosomes are consisted of 5 snRNPs (small nuclear ribonucleoproteins; U1, U2 U4/U6, U5) and many auxiliary proteins to specifically recognize the splicing site which results in the catalysis of splicing reaction [48,51,52]. During the splicing, several molecular events take place as (1) U1 snRNA pairs with the 5′ end of the splice site; (2) splice factor 1 binding to branched point; (3) U2 auxiliary factor (U2AF) heterodimer consisting of U2AF65 and U2AF35 to polypyrimidine tract, and 3′ end AG. This results in the formation of the E complex and is changed in an ATP-dependent prespliceosome A complex after the removal of SF1 by snRNP [48,51,52]. Later on, U4/U6-U5 complex resulted in a B-complex leading to conformational structural changes to generate an active C complex. The process of alternative splicing comprises of the many patterns viz. exon skipping, 3′ and 5′ alternative selection, intron retention, etc. Moreover, other events which affect the outcome of transcript isoform include alternative promoter usage, alternative polyadenylation, and mutually exclusive exons [53]. Alternative splicing is not a random process but it is highly controlled by regulatory proteins known as trans-acting proteins including activators and repressors as well as cis-acting regulatory elements like enhancers and silencers [54]. The splicing enhancer or repressor proteins bind to their specific sites on the pre-mRNA located in the exonic and intronic region and are known as exonic splicing enhancer (ESE), intronic splicing enhancer (ISE), and exonic splicing silencer (ESS), intronic splicing silencer (ISS), respectively [55].
Transcription factors
The regulation of transcription takes place at two levels. The first level comprises the TFs and the transcription apparatus while the second level comprises the chromatin and other related regulators. The TFs are therefore categorized into two classes attributing to their regulatory responsibilities of either initiation or elongation control, and some of them can play both roles [56]. TFs generally bind to cofactors, namely, coactivators and corepressors, which are protein complexes aiding in activation and repression, respectively [57]. These cofactors themselves do not possess any DNA-binding properties. A large number of TFs are considered to play a role in the process of transcription initiation, and this is done by them recruiting certain coactivators [4]. Some examples of coactivators include p300, the mediator complex, and some other general TFs [26–29]. Among them, the mediator complex, in recent studies has emerged as an important integrator of information from the activators, repressors, many signaling pathways, and even other regulators when transitioning between transcriptional initiation and elongation [30–36]. TFs are known to control genome-wide transcription through enhancer elements while recruiting coactivators and RNA polymerase II. Deregulation of the transcriptional regulator is associated with several diseases like cancer, diabetes, neurological disorders, etc.
Super-enhancers
Gene expression is an unambiguously regulated phenomenon both in a cell type and stage-specific pattern which mainly depends on the interaction between regulatory cis-elements and trans-acting factors. Enhancers belong to the family of regulatory DNA sequence which activate transcription of their associated gene up to a distance of 1 million of base-pair irrespective of its location and position from the transcription start site [58]. The binding of a TF with enhancer elements results in the recruitment of coactivators, mediator (MED) complexes, p300, and CREB-binding protein (CBP) [59]. Further, these interactions are known to form a complex with the TFs, activators, enhancers, core promoter region, and the RNA polymerase to start the transcription [60]. In the last decade, super-enhancers are emerging as an important regulator of transcription and gene expression [60]. Super-enhancers are the large and hyperactive genomic regions that exist in the mammalian genome to drive the transcription of a variety of genes linked with cellular identity and disease [60,61]. The three major traits of enhancers that form super-enhancers are: (1) clustering in genomic proximity, (2) extraordinary signal of transcription-regulating proteins, and (3) high frequency of physical interaction with each other [60]. In eukaryotes, TFs can be densely bound with enhancers in a combinatorial and synergistic manner for their regulatory activity. Interestingly, the super-enhancers are densely occupied and cooccupied by a large number of master TFs and the mediator complex, hence able to establish an auto-regulatory network. For an instance, in mouse embryonic stem cells, pluripotent TFs like Oct4, Sox2, and Nanog are identified to occupy super-enhancers at extremely high levels. Also, the higher occupancy of many TFs and cofactors has been noticed in the super-enhancers such as CDK7 and BRD4. However, very little is known about how tissue-specific super-enhancers are now emerging to be critical for lineage commitment during cellular development. Interestingly, super-enhancer-associated genes are reported with higher expression compared to the genes with regular enhancers. This is true in a variety of human cancers.
Dysregulation of transcriptional regulators in diabetes
Diabetes mellitus stands to be a group of metabolic diseases wherein an individual has consistently elevated levels of blood sugar due to either of the two reasons, insufficient production of insulin by the pancreas or improper response to the produced insulin. Several mutations have been noticed TFs-related to pancreas and their binding sequences implicated in diabetes. TFs including HNF1α, HNF4α, NeuroD1, HNF1β, and PDX1 control the gene expression of pancreatic cells and mutations in any of these factors can cause diabetes [62]. High mobility group A1 (HMGA1), a nonhistone protein acts as regulator of chromatin structure and transcription. HMGA1 also acts as a downstream target of insulin receptor (INSR) signaling, thereby controling the action and function of insulin. The lack of HMGA1 is associated with diabetes in mice and humans.
Dysregulation of transcriptional regulators in human cancers
Cancer refers to the abnormal and unregulated growth of cells that may or may not lead to tumor formation. Genetic regulation and its impairment are one of the most prominent and critical factors that lead to dreaded diseases like cancer.
Chromatin regulators
A variety of mutations in chromatin regulators are involved in human malignancies by transcription and gene expression. Loss of function mutations are reported in chromatin remodeling proteins like SMARCA4, SMARCB1, and ARID1A and are associated with multiple types of cancer. Mutations in polycomb genes like EZH2 and SUZ12 and DNA methylation apparatus led to cancer. This suggested that gene silencing contributes to tumorigenesis. Moreover, over-expression of SetDB1, a histone H3K9 methyltransferase can be seen in the majority of malignant melanomas which in turn contributes to gene activation in lung cancer and melanoma.
DNA methylation
The hypermethylation of CpG sites is more often associated with the inactivation of tumor suppressor genes associated with cellular proliferation. Several groups have demonstrated that promoter-associated CpG islands undergo abnormal DNA hypermethylation in cancers [63,64]. Hypermethylation of glutathione S-transferase P (GSTP1) has been shown in prostate cancers, p16INK4a in 20% of the patients with lung cancer, and BRCA1 in breast and ovarian cancers [65–67]. Interestingly, the increased frequency of p16INK4a and GSTP1 hypermethylation was positively associated with disease progression, indicating the significance of DNA hypermethylation in the development and progression of human cancer. Moreover, CpG Island methylator phenotypes were observed in colon cancer and glioblastoma. Mutations in the DNMT3A, IDH1, TET1, IDH2, and TET2 are more frequent in leukemia. DNMT3A mutations are associated with a worse prognosis, aggressive disease, and resistance to therapies [68–70].
N6-methyladenosine (m6A)
Recently, m6A modifications are observed with their prominent role in cancers through m6A modifications introduced by the writer in the mRNA of tumor suppressors and oncogenes and then recognition of these marks by readers either to increase the expression of oncogene expression or silence the expression of tumor suppressors. For example, METTL3-enhanced mRNA methylation and stability of SOX2 to maintain the radio-resistance of glioma stem cells [71]. Silencing of METTL3 restored the sensitivity of gemcitabine, 5-fluorouracil in pancreatic cancer. METTL14 displayed suppressed self-renewal and tumorigenicity of glioma stem cells [72]. ALKBH5 overexpression enhanced the anticancer activity of gemcitabine by suppressing the dependency of m6A WNT inhibitory factor 1 (WIF-1) in pancreatic cancers. On the other hand, ALKBH5 is robustly expressed in glioma stem cells and knockdown of ALKBH5 decreased the growth of the glioma stem cells.
Noncoding RNAs
Altered expression of a variety of ncRNAs has been observed in human malignancies and these ncRNAs changed the expression of genes associated with cancer progression, metastasis, and drug resistance. Few well known examples are: (1) ANRIL lncRNA as a transcriptional repressor of members of the INK4a/ARF/INK4b locus in many cancer types. ANRIL recruit polycomb repressive complexes 1 and 2 to silence the function of tumor suppressors.
Alternative splicing
In the past decade, several groups have shown that either somatic mutations or abnormal expression levels of spliceosomes and splicing factors in the alternative splicing machinery are associated with human malignancies including myelodysplastic syndrome, acute myeloid leukemia, breast, colon, cervical, liver, ovary, thyroid, and chronic myelogenous leukemia [68,73–77]. The majority of these alterations affects canonical RNA splicing, mRNA maturation, splicing of pre-mRNA, mRNA decay, and exon-intron retention which can directly influence the transcription process leading to the development of human malignancies.
Misregulation of transcription factors (TFs) and mediator coactivation complex
Mutations in several TFs have long been found to play an essential role in tumorigenesis. In the last decade, exome sequencing studies have confirmed the oncogenic mutation or overexpression in key TFs such as TP53, c-MYC, NF-κB, STAT3, CEBP-α, TAL-1, and β-catenin in human malignancies. TP53 somatic mutations and deletions are one of the most frequent mutations in human cancers including lung, ovarian, colorectal, thyroid, esophageal, head and neck, cervical, sarcoma, leukemia, melanoma, etc. MYC is a robustly expressed and highly amplified oncogene in solid tumors and leukemia. MYC translocations are more common in patients with multiple myeloma MYC. Constitutive activation of NF-κB has been observed in cancers either because of inflammatory microenvironment or oncogenic mutations. The NF-κB activity can enhance proliferation, angiogenesis, and epithelial-mesenchymal transition and inhibit apoptosis to increase tumorigenesis and metastasis. STAT3 is mainly upregulated in all the major cancer types and regulates immune and inflammatory responses in the tumor microenvironment through interleukins (IL-6, -17, -10, -23, -17, 23), chemokines like CXCL12, and COX-2. Mutations in β-catenin and its signaling cascade lead to translocation of β-catenin in the nuclear compartment to transcriptionally activation of genes associated with cancer stemness, metastasis, and drug resistance. Moreover, over-expression of TAL1, the oncogenic TF was noticed in ∼ 50% of the patients with T-cell acute lymphoblastic leukemia (T-ALL) cases by altering regulatory signaling cascades that drive the T-ALL oncogenesis. Somatic mutations in the mediator coactivator complex have been reported to the progression and development of human cancers. Mutations in MED12 are associated with prostate cancer. Collectively, these alterations in the TFs exert their oncogenic effect either due to enhancing or repressing the transcription of the genes involved in key oncogenic processes.
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Section II
Transcriptional and translational regulators in cancer
Chapter 2: Role of alternative splicing in health and diseases
Harsh Sharma; Kusum Yadav; Ravi Datta Sharma Amity Institute of Integrative Science and Health, Amity University Haryana, Manesar, Haryana, India
Abstract
Alternative splicing (AS) is a characteristic of many genes, in which several different transcripts can be originated from the same primary mRNA. These variants are called transcripts or isoforms. AS provides the required diversity to apply gene products in different conditions or tissues. More than 90% of human intron-containing genes undergo AS. Furthermore, these genes are thought to encode two or more isoforms, which are diversified across tissues and developmental stages. Each biological function role of our body like cell death, controlling cell division, control of gene expression is played by AS. Different heritable diseases are either related to irregular/abnormal AS or resulted from irregular/abnormal AS. And about half of the genetic disorders which are inherited are related to SNPs that are also the result of wreckage of splicing events. Profiling normal and disease tissues shows significant changes in AS related to the progression of disease. Genome-wide platforms for assessing AS are a powerful tool for understanding the pathological role of this process. Abnormal AS has been related to several diseases, including cancer. AS is a potential target for therapeutics, and there is active research on finding new biomarkers. Finding disease specific biomarkers might allow; early diagnosis of diseases and their prevention strategies to assure healthy longevity, and identification of personalized medicine. This chapter lightens about basic of gene expression, regulation via AS, regulators of AS, technique to assess the AS, brief overview of various algorithms for finding AS, and role of AS in disease.
Keywords
Gene expression; Alternative splicing; Disease; Cancer; Splicing factor; Microarrays; RNA-sequencing
Introduction
Gene expression
Each species of living organisms possesses some unique characters for development and inheritance. These characters are transferred from one offspring to another in the form of the deoxyribonucleic acid (DNA) present in their cells. The four bases of DNA-adenine (A), thymine (T), guanine (G), and cytosine (C)—can code the huge amount of information required to build an organism. The pairing between A and T and G and C are complementary in such a fashion that each base at one strand of the DNA is bound with a complementary base at the opposite strand via hydrogen bonds. Furthermore, the DNA molecule is packaged into a complex structure called a chromosome with the help of several proteins. Genes encipher proteins and then proteins instruct cell to function. The genetic code stored in DNA directs the assembly of protein molecules, which in turn dictate cell functions. Cells can have distinct functions and appearance due to their ability to use the different stretches of DNA, which are known as genes. These genes are decoded in a linear fashion in order to produce a functional cellular product in a process called gene expression or central dogma. The phenomenon of gene expression is a central node of life in living organisms. Cellular organisms are divided into prokaryotes (no differentiated nucleus) and eukaryotes (differentiated nucleus in a cell). In eukaryotes, the genome of each cell does not usually change throughout its existence. A