Histone Modifications in Therapy

Histone Modifications in Therapy provides an in-depth analysis of the role of histone mechanisms in major diseases and the promise of targeting histone modifications for disease prevention and treatment. Here, researchers, clinicians and students will discover a thorough, evidence-based discussion of the biology of histones, the diseases engaged by aberrant histone modifications, and pathways with therapeutic potential. Expert chapter addresses the role of histone modifications across a variety of disorders, including cancer, neuropsychiatric, neurodegenerative, cardiac, metabolic, infectious, bacterial, autoimmune and inflammatory disorders, among others. In relation to these disease types, histone modifications are discussed, both as mechanisms of prevention and possible treatment.

A concluding chapter brings together future perspectives for targeting histone modifications in therapy and next steps in research.

• Examines the use of histone modifications in disease prevention and therapy
• Explores the role of histone modifications in cancer, neuropsychiatric, neurodegenerative, cardiac, metabolic, infectious, bacterial, and inflammatory disease, among others
• Features chapters from a broad range of international authors and disease specialists

• Language: English
• Publisher: Academic Press
• Release date: Aug 21, 2020
• ISBN: 9780128167403

Book preview

Histone Modifications in Therapy

First Edition

Pedro Castelo-Branco

Carmen Jeronimo

Series Editor

Trygve Tollefsbol

Table of Contents

Cover image

Title page

Copyright

Contributors

Editors biography

Links

Preface

Chapter 1: Histone modifications in diseases

Abstract

1.1: The basics of histone modifications

1.2: Alterations of histone modifications in human diseases

Section I: Targeting histone modifications for cancer treatment

Chapter 2: HDAC inhibitors in cancer therapy

Abstract

2.1: HDACs: The most successful epigenetic drug discovery target

2.2: Clinically approved HDAC inhibitors

2.3: Hydroxamic acid HDAC inhibitor clinical candidates

2.4: Nonhydroxamic acid HDAC inhibitor clinical candidates

2.5: HDAC inhibitors in combination with cytotoxic agents

2.6: HDAC inhibitors in combination with targeted therapy

2.7: Combination epigenetic therapy

2.8: Dual mechanism HDAC inhibitors

2.9: HDAC inhibitors: Magic bullets or shotgun pellets

Chapter 3: HAT inhibitors in cancer therapy

Abstract

3.1: Background

3.2: HAT superfamilies

3.3: HATs and cancer

3.4: HATs and other diseases

3.5: HAT inhibitors

3.6: Bi-substrate inhibitors

3.7: Natural products and derivatives

3.8: Synthetic inhibitors

3.9: Conclusions and perspectives

Chapter 4: Targeting DOT1L for mixed-lineage rearranged leukemia

Abstract

Acknowledgment

4.1: Introduction

4.2: The chemical inhibitors of DOT1L

4.3: Biological assays to screen for new DOT1L inhibitors

4.4: Filter-binding assay

4.5: Scintillation proximity assay

4.6: Surface plasmon resonance

4.7: Isothermal titration calorimetry

4.8: Cellular thermal shift assay

4.9: Cell proliferation inhibition assay

4.10: Quantitative reverse transcriptase PCR

4.11: High content screening

4.12: Conclusions and perspectives

Chapter 5: BET mechanisms in cancer

Abstract

Acknowledgments

Declaration of interests

5.1: Introduction

5.2: BET proteins initiate protein-protein interactions

5.3: Roles of BET in cellular homeostasis

5.4: Pharmacological targeting of BET bromodomains

5.5: NUT midline carcinoma

5.6: Acute myeloid leukemia (AML)

5.7: Multiple myeloma

5.8: Neuroblastoma

5.9: Glioblastoma

5.10: Colorectal cancer

5.11: Ovarian cancer

5.12: Breast cancer

5.13: Melanoma

5.14: Prostate cancer

5.15: Lung cancer

5.16: Endometrial cancer

5.17: Liver cancer

5.18: Head and neck cancer

5.19: Emerging consensus on BET-targeted phenotypes and mechanisms

5.20: Toxicity arising from BET bromodomain targeting in cancer

5.21: Resistance to BET bromodomain inhibitors

5.22: Combinatorial strategies and efforts to overcome resistance

5.23: BET protein degraders

5.24: Alternative BET targeting

5.25: Conclusions and outlook

Chapter 6: Histone demethylase inhibitors and their potential in cancer treatment

Abstract

6.1: Introduction

6.2: Arginine demethylation

6.3: Lysine demethylation

6.4: Conclusions

Chapter 7: Targeting chromatin remodelers in urological tumors

Abstract

Acknowledgments

7.1: Introduction

7.2: Targeting chromatin remodelers in kidney cancer

7.3: Targeting chromatin remodelers in bladder cancer

7.4: Targeting chromatin remodelers in prostate cancer

7.5: Targeting chromatin remodelers in testicular cancer

7.6: Conclusion: Clinical trials in urological tumors

Section II: Targeting histone modifications for infectious disease

Chapter 8: The therapeutic potential of epigenetic manipulation during infectious diseases

Abstract

8.1: Introduction

8.2: Epigenetic modifications

8.3: Pathogen-driven epigenetic modifications

8.4: Host immune response and epigenetic changes in response to infection

8.5: Therapeutic potential of epigenetic drugs in infectious diseases

8.6: A view of the future

Chapter 9: Targeting histone deacetylases for bacterial infections

Abstract

Funding

9.1: Introduction

9.2: HDACs in epigenetic and nonepigenetic regulation

9.3: HDACi as antiinflammatory agents

9.4: HDAC regulation by bacterial pathogens

9.5: Effects of HDACi on cell responses to bacterial agonists

9.6: HDACi in cellular infection models

9.7: HDACi in animal models of infection

9.8: Conclusions

Chapter 10: Targeting histone epigenetics to control viral infections

Abstract

10.1: Chronic viral infections

10.2: Cancer-inducing viruses

10.3: Epidemic/emerging viral infections

10.4: Conclusion and future perspectives

Section III: Targeting histone modifications for treating other pathologies

Chapter 11: Targeting histone modifications in psychotic disorders

Abstract

Acknowledgments

11.1: Introduction

11.2: Histone modifications in psychotic disorders

11.3: Drugs targeting histone modifications in psychotic disorders

11.4: Histone-modifying drugs for correcting cognitive deficits in psychotic disorders

11.5: Conclusions

Chapter 12: Epigenetic treatment of neurodegenerative disorders

Abstract

12.1: Introduction

12.2: Histone modifications

12.3: Histone modifications in neurodegenerative disorders

12.4: Histone modification treatments in neurodegenerative disorders: Preclinical studies

12.5: Histone-modification treatment in neurodegenerative disorders: Clinical studies

12.6: Conclusions

Chapter 13: Histone modification as a potential preventative and therapeutic approach for cardiovascular disease

Abstract

13.1: Introduction

13.2: Histone acetylation and deacetylation in cardiovascular disease

13.3: Histone methylation in cardiovascular disease

13.4: Conclusions and future perspectives

Chapter 14: The potentiality of histone deacetylase inhibitors for diabetes and obesity

Abstract

14.1: Introduction

14.2: Epigenetic role in insulin production

14.3: Interplay of epigenetics and obesity

14.4: Epigenetic modifiers and diabetes

14.5: Epigenetic modifiers and the complications of diabetes

14.6: Histone deacetylase inhibitors and obesity

14.7: Epigenetic modifiers and the complications of obesity

14.8: Histone deacetylase inhibitors as a double hit for obesity and diabetes

14.9: Conclusion

Chapter 15: Targeting histone modifications in cancer immunotherapy

Abstract

15.1: Introduction

15.2: Epigenetic remodeling in TME

15.3: Epigenetic immunomodulation in TME players

15.4: NK cells

15.5: Macrophages

15.6: Dendritic cells

15.7: Other immune cell players

15.8: Cancer-associated fibroblasts

15.9: Tumor endothelial cells

15.10: Modulating epigenetics of the TME-Cancer cell interaction: Can we change the game rules?

Chapter 16: Epigenetic drug development for autoimmune and inflammatory diseases

Abstract

16.1: Introduction

16.2: Pathogenesis of autoimmune and inflammatory disorders

16.3: Epigenetic drug development for autoimmune and inflammatory disorders

16.3.3: Synthetic histone modification regulators

16.4: Conclusion

Chapter 17: Present and future perspectives for targeting histone modifications in therapy

Abstract

17.1: Introduction

17.2: Targeting the epigenetic writers

17.3: Targeting the epigenetic readers

17.4: Targeting the epigenetic erasers

17.5: Histone deacetylase inhibitors (HDACi)

17.6: Conclusions

Funding

Index

Copyright

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Contributors

Hélder Almeida-Lousada

Algarve Biomedical Center, Campus Gambelas

Centre for Biomedical Research (CBMR), Universidade do Algarve

Department of Biomedical Sciences and Medicine, Universidade do Algarve, Faro, Portugal

Lucia Altucci     Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy

Paola B. Arimondo     Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, UMR3523 CNRS, Paris, France

Alexandra Binnie

William Osler Health System, Toronto, ON, Canada

Algarve Biomedical Centre, Faro, Portugal

Corentin Bon

Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, UMR3523 CNRS

Ecole Doctorale MTCI, Université de Paris, Sorbonne Paris Cité, Paris, France

Ramon Cacabelos     Department of Genomic Medicine, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain

Vânia Camilo     Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal

Pedro Castelo-Branco

Algarve Biomedical Center, Campus Gambelas

Centre for Biomedical Research (CBMR), Universidade do Algarve

Department of Biomedical Sciences and Medicine, Universidade do Algarve, Faro, Portugal

Claudia C. dos Santos

Keenan Research Centre for Biomedical Science, St. Michael’s Hospital

Institute of Medical Sciences, Department of Medicine, University of Toronto, Toronto, ON, Canada

Marta Dueñas

Biomedical Research Institute I+12, University Hospital

Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas)

Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

Ahmed El-Serafi     Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden

Ibrahim El-Serafi     Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

Bradley S. Ferguson

Center of Biomedical Research Excellence for Molecular and Cellular Signal Transduction in the Cardiovascular System

Department of Nutrition, University of Nevada, Reno, Reno, NV, United States

Mónica T. Fernandes

School of Health, Universidade do Algarve

Algarve Biomedical Center, Campus Gambelas

Centre for Biomedical Research (CBMR), Universidade do Algarve, Faro, Portugal

Panagis Filippakopoulos

Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research

Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom

Francesco Fiorentino     Department of Chemistry, University of Oxford, Oxford, United Kingdom

A. Ganesan     School of Pharmacy, University of East Anglia, Norwich, United Kingdom

Aleksander M. Grabiec     Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland

Justine S. Habibian

Cellular and Molecular Biology

Center of Biomedical Research Excellence for Molecular and Cellular Signal Transduction in the Cardiovascular System, University of Nevada, Reno, Reno, NV, United States

Elizabeth Henderson

Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research

Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom

Rui Henrique

Department of Pathology, Portuguese Oncology Institute of Porto (IPOP)

Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP) & Porto Comprehensive Cancer Center (P.CCC); Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal

Georges Herbein

Department Pathogens & Inflammation-EPILAB, UPRES EA4266, University of Franche-Comté, University of Bourgogne Franche-Comté

Department of Virology, CHRU Besancon, Besançon, France

Carmen Jerónimo     Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto; Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal

Haroon Khan     Department of Pharmacy, Faculty of Chemical & Life Sciences, Abdul Wali Khan University, Mardan, Pakistan

Katarzyna B. Lagosz     Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland

João Lobo

Department of Pathology, Portuguese Oncology Institute of Porto (IPOP)

Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (GEBC CI-IPOP) & Porto Comprehensive Cancer Center (P.CCC)

Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal

Antonello Mai     Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Rome, Italy

Olaia Martínez-Iglesias     Department of Medical Epigenetics, Euroespes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain

Ester Munera-Maravilla

Biomedical Research Institute I+12, University Hospital

Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas)

Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

Angela Nebbioso     Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy

Zeina Nehme

Department Pathogens & Inflammation-EPILAB, UPRES EA4266, University of Franche-Comté, University of Bourgogne Franche-Comté, Besançon, France

Lebanese University, Beirut, Lebanon

Jesús M. Paramio

Biomedical Research Institute I+12, University Hospital

Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas)

Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

Sébastien Pasquereau     Department Pathogens & Inflammation-EPILAB, UPRES EA4266, University of Franche-Comté, University of Bourgogne Franche-Comté, Besançon, France

Jacob Peedicayil     Department of Pharmacology & Clinical Pharmacology, Christian Medical College, Vellore, India

Anju M. Philip

Zebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital

Department of Physiology, University of Toronto, Toronto, ON, Canada

Dante Rotili     Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Rome, Italy

Federica Sarno     Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy

Yang Si     Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, UMR3523 CNRS, Paris, France

Hammad Ullah     Department of Pharmacy, Faculty of Chemical & Life Sciences, Abdul Wali Khan University, Mardan, Pakistan

Editors biography

Pedro Castelo-Branco completed his Doctorate in molecular biology at Oxford University in 2005, followed by postdoctoral fellowships at Harvard University and the University of Toronto. Since 2014, he is a Professor in the Department of Biomedical Sciences and Medicine and head of the Epigenetics in Human Disease Laboratory, at the University of Algarve. His scientific interests include the identification of specific epigenetic signatures throughout carcinogenesis and targeted methylation/demethylation as a therapeutic approach.

Carmen Jerónimo is Group Leader of the Cancer Biology & Epigenetics Group and the Scientific Coordinator of the Biobank at the Portuguese Oncology Institute of Porto (IPO Porto) as well as Invited Associate Professor in the Department of Pathology and Molecular Genetics and the Director of the Master Course in Oncology at the University of Porto, teaching Pathology and Cancer Epigenetics, both undergraduate and postgraduate courses.

She obtained her BSc in Biology (1994), MSc in Oncology (1998), PhD in Biomedical Sciences (2001), and Habilitation in Pathology and Molecular Genetics (2011) at the University of Porto. She performed her PhD project at Johns Hopkins University (JHU), United States under the GABBA Program, working on prostate cancer genetic and epigenetic alterations. From 2002 until 2007, she was a postdoctoral fellow and Invited Researcher at IPO Porto, in collaboration with JHU, working on detection of neoplastic cells by DNA-based technology in clinical samples obtained from noninvasive or minimal invasive methods. In 2008, she established her independent group at IPO Porto, working on Cancer Biology and Epigenetics (FCT-2008 Science Program).

She has supervised 4 PhD students and cosupervised 5 PhD students, as well as supervised 36 master students and several undergraduate students. Presently she mentors three junior researchers, one postdoctoral, three PhD students, and four master students.

As an independent Researcher, she served as Principal Investigator of 20 grants, and participated in other 14 projects granted from different National and International agencies under competitive concurrence (total amount 2.3 K€).

She has authored or coauthored more than 160 international scientific publications including 5 book chapters and 39 review articles (H-index 43; Scopus 02/2020), including in first quartile (Q1) journals; Clin Cancer Res, Cancers, Cancer Letters, Cell Death Dis, Br J Cancer, Eur J Cancer, J Cell Mol Med, J Hematol Oncol, JNCI, Mol Cancer, Mol Oncol and Nat Commun, Oncogene, and PNAS. She has collaborated in a patent submission (Methods and biomarkers for detection of bladder cancer. US 20130210011/EP 2630261 A1/WO 2012052844 A1).

Her research interests are focused on the characterization of the epigenome of tumor cells, and the identification of functional changes involved in cell epigenetic homeostasis breakdown. In the context of Personalized Medicine, she works in the development of new cancer epigenetic biomarkers based in liquid biopsies as well as in the drug discovery based on modulation of epigenetic aberrations. Owing to the relevance that Immuno-oncology has demonstrated in recent years, she is also investigating the epigenetic expression modulation of biomolecules involved in immune checkpoint regulation, aiming at the improvement of immunotherapeutic strategies by combination with epi-drugs. More recently, she started tackling the contribution of deregulated noncoding RNAs and its interaction with other epigenetic mechanisms in malignant transformation.

Currently, she serves as Section Editor of Clinical Epigenetics and a Associate Editors of International Journal of Molecular Sciences and Epigenomes, and she is also MC member of COST Action European Epitranscriptomics Network-CA16120-EPITRAN and Board member of ESUR-Section of Urological Research (ESUR) of European Association of Urology (EAU).

She usually acts as a Grant Reviewer for multiple national (FCT Investigator Call 2013 e 2015) and international agencies (2003-Health Research Board-HRB)-IR; 2006-Associazione Italiana per la Ricerca sul Cancro; 2006, 2007-National Medical Research Council, Singapore; 2007, 2015-Cancer Research, UK; 2010-Binational Science Foundation, Israel; 2011, 2016, 2018-Swiss National Science Foundation-SNSF; 2012-Williams Barker, MRC, UK; 2013, 2015-Swiss League Against Cancer-KFS; 2013, 2015-FWF Austrian Science Fund; 2014-Prostate Cancer, UK; 2016, 2017-Fund for Scientific Research-FNRS-BL; 2019-Agence Nationale de la Recherche, FR; 2019-Fundaciò La Marató, SP.

Links

http://www.ipoporto.pt/en/ensino-investigacao/grupo-de-epigenetica-biologia-do-cancro/

http://orcid.org/0000-0003-4186-5345

Preface

Pedro Castelo-Branco; Carmen Jerónimo

Histone posttranslational modifications belong to the rather fascinating world of epigenetics and constitute an important level of gene expression regulation in the human cells, and, consequently tissues and body. Remarkably, these covalent modifications have a unique feature, the reversibility.

This book will offer a comprehensive view of the biology of histones, the diseases caused by aberrant histone modifications profile, and pathways/molecules potentially targetable. It comprises 17 chapters accommodated in 3 major sections devoted to the current knowledge on targeting histone modifications in the most currently relevant diseases, including cancer (Section I), a major health concern worldwide; infection diseases (Section II); and other pathologies (Section III) such as cardiovascular, diabetes, psychotic and neurodegenerative diseases, and importantly, autoimmune and inflammatory disorders. Expert chapter authors address the role of histone modifications across each disorder and identify possible targetable molecules with potential clinical application, also discussing the mechanisms of action. A final chapter brings together present and future perspectives for targeting histone modifications mostly based on malignant diseases, as these are the ones in the forefront of knowledge on histone modifications therapy.

Histone Modifications in Therapy will provide researchers, clinicians, and students with basic and translational evidence for the role of histone modifications in disease prevention and treatment.

Chapter 1: Histone modifications in diseases

Mónica T. Fernandesa,b,c; Hélder Almeida-Lousadab,c,d; Pedro Castelo-Brancob,c,d    a School of Health, Universidade do Algarve, Faro, Portugal

b Algarve Biomedical Center, Campus Gambelas, Faro, Portugal

c Centre for Biomedical Research (CBMR), Universidade do Algarve, Faro, Portugal

d Department of Biomedical Sciences and Medicine, Universidade do Algarve, Faro, Portugal

Abstract

Epigenetics comprises heritable changes in gene expression that are not derived from DNA sequence alterations. A major epigenetic mechanism involves the posttranslational modification of histones where specific target residues can be methylated, acetylated, phosphorylated, or ubiquitinated by specific enzymes, contributing to chromatin dynamics and the control of gene expression. Importantly, altered histone modifications have been implicated in the pathogenesis of an increasing number of diseases, including cancer, wherein such alterations are considered a hallmark of carcinogenesis. Also, they are increasingly being described in infectious, psychiatric, and neurodegenerative diseases, as well as in autoimmune/inflammatory diseases. Although less studied, cardiovascular and metabolic diseases are also affected by histone modification alterations. Therefore the reversibility of histone modifications offers a great opportunity to develop new strategies for the early prevention and treatment of a wide range of diseases.

Keywords

Epigenetics; Histone modifications; Chromatin; Gene expression; Diseases; Targeted therapies

1.1: The basics of histone modifications

Misregulation of gene expression is implicated in the pathogenesis of diverse human diseases.¹ It can be triggered by genetic alterations, including gene mutations, amplifications, and translocations, and epigenetic alterations, which are also inherited but do not involve changes in the DNA sequence. In fact, a growing body of evidence suggests that epigenetic alterations, affecting mainly noncoding RNAs, DNA methylation, and posttranslational histone modifications, can significantly modify pivotal transcriptional programs.¹,² Both DNA methylation and histone modifications modulate gene expression chiefly because they impact the chromatin structure.³,⁴

Chromatin is the DNA–protein complex found in the eukaryotic cell nucleus, and its primary function is packaging DNA molecules into a more compact, denser shape. The basic repeating unit of chromatin is the nucleosome, which is composed of 146 base pairs of DNA wrapped around an octamer containing two of each core histone H2A, H2B, H3, and H4.⁵,⁶ DNA is negatively charged due to the phosphate groups in its phosphate-sugar backbone. However, the amino acids lysine and arginine are preponderant in each of the core histones, and their positive charges can effectively neutralize the negatively charged DNA backbone, making the interaction between histones and DNA very tight.⁵ Nucleosomes are then connected by a linker DNA of varying length, which is further folded into arrays with the aid of the linker histone H1 and nonhistone proteins to form a 30-nm chromatin fiber.⁶–⁸ This ordered structure enables the necessary compaction to fit the large eukaryotic genomes inside the cell nuclei,⁹ prevents DNA damage, and regulates DNA replication, cell division, and gene expression.¹⁰,¹¹

Gene expression requires the two strands of DNA to separate temporarily, allowing the access of enzymes involved in transcription to the DNA template. Therefore, although compact, the structure of chromatin must be highly dynamic, switching between an open and a closed state that regulates the access to the underlying DNA in interphase. Where the chromatin is loosely organized, it is more accessible for transcription and is referred to as euchromatin. However, chromatin can also be highly compacted and inaccessible for transcription in a closed or inactive state, the so-called heterochromatin. Therefore genes are coordinately activated or repressed to ensure cellular homeostasis where the chromatin switches between euchromatin and heterochromatin.⁶

In addition to some spontaneous DNA unwrapping and rewrapping in the nucleosome, there are other relevant mechanisms to allow access to the DNA by modulating the chromatin structure. First, chromatin structure is thought to be influenced by DNA methylation, the most abundant epigenetic modification, which involves the addition of a methyl group to the cytosine pyrimidine ring in CpG dinucleotides by DNA methyltransferases (DNMTs). Although the mechanisms involved remain largely unknown,¹² DNA methylation has been associated with nucleosome positioning/remodeling,¹³ the recruitment of methyl-binding domain proteins (MBDs),¹⁴ and the binding of CTCF factors,¹⁵ thus modifying the chromatin structure. Second, and more important in the context of this book, core histone modifications are pivotal to chromatin structure and dynamics. Histone modifications also work jointly with DNA methylation for repression of gene loci.¹⁶,¹⁷

Histones are a family of small, positively charged proteins, which are among the most highly conserved eukaryotic proteins. As previously mentioned, the core histones are responsible for the chromatin packing in nucleosomes. These are composed of two main domains: the histone fold that is inserted in the nucleosome and is important for histone/histone and histone/DNA interactions, and an N-terminal tail, which extends out from the DNA–histone core.⁵ The histone tails are subject to several different types of enzyme-catalyzed, posttranslational covalent modifications on specific residues that alter their interaction with DNA and nuclear proteins and, in turn, control critical aspects of chromatin structure and function.

The most well-studied types of histone modifications are methylation, acetylation, phosphorylation, and ubiquitination.¹⁸ All these types of modifications are reversible, with one highly specific enzyme serving to create a particular type of modification and another to remove it. These enzymes are recruited to specific sites in the chromatin.

Histone methylation involves the addition of one, two, or three methyl groups to lysine residues, and one or two methyl groups to arginine residues. Methyl groups can be added by a set of different histone methyltransferases (HMTs) and removed by histone demethylases (HDMs). Histone methylation in specific lysines and arginines has been reported to regulate gene expression, either promoting or counteracting it, in different settings.¹⁹ For example, trimethylation of histone H3 at lysines 9, 27, and 20 is often associated with repressed transcription, whereas methylation of lysines 4, 36, and 79 correlates with active transcription.²⁰

Histone acetylation is associated with the transfer of the acetyl group from acetyl-coenzyme A to the target lysine residue. Generally, high levels of histone acetylation are associated with euchromatin²¹,²² and are also prevalent in active promoter regions and enhancer elements.²³,²⁴ Acetyl groups are added to specific lysines by different histone acetyltransferases (HATs) and removed by various histone deacetylase complexes (HDACs).²¹

Histones are phosphorylated by the addition of a phosphate group, most commonly to tyrosine, threonine, and serine residues, where it influences processes such as DNA repair, cell division, and gene regulation. Recently, phosphorylation of histone H1 linker was also reported to promote chromatin decondensation.²⁵ Several distinct kinases are required for the phosphorylation of histones on different residues.

Finally, histones can also be ubiquitinated in lysines. Histone ubiquitination is catalyzed by the formation of an isopeptide bond between the carboxy-terminal glycine of ubiquitin and a lysine residue on histones. This bond is developed by the sequential intervention of E1-activating and E2-conjugating enzymes and E3 ligases. Ubiquitination of lysine residues on histones was reported to be involved in DNA repair, heterochromatin maintenance, and gene regulation. For example, monoubiquitinated histone H2B was shown to be associated with the transcribed region of highly expressed genes in human cells.²⁶ Histone ubiquitination can be reversed by deubiquitinases.²⁷,²⁸

In general, there are two ways in which histone tail modifications affect gene expression. First, they can directly modulate chromatin structure dynamics likely due to alterations in histone tail charges caused by the modifications, which influence the interaction between histones and DNA, and between nucleosomes. For instance, addition of an acetyl group is a modification that neutralizes the positive charge of the target lysine.¹⁸ This reduces the attraction between the histone and the negatively charged DNA backbone, thereby reducing the affinity of the histone tails to adjacent nucleosomes. Second, they can create a binding site and recruit specific proteins to the modified stretch of chromatin. These proteins are important epigenetic players that are categorized as writers (e.g., HMTs, HATs, and kinases), which introduce various chemical modifications on DNA and histones; readers, which identify and interpret those modifications; and erasers (e.g., HDMs, HDACs, and deubiquitinases), which remove the chemical tags. In general, the recruited proteins act with the modified histones to determine how and when genes will be expressed.²⁹,³⁰ For example, the addition of one, two, or three methyl groups to lysine has little effect on the chemistry of the histone, but proteins containing specific domains, including Tudor, chromo, or PHD, can recognize and bind lysine-methylated residues and recruit various chromatin-remodeling complexes, thereby regulating the chromatin structure and gene expression.¹⁹,³¹

So far, numerous histone modifications have been described and dozens of different residues reported to be altered, but a functional understanding of several modifications, alone or in combination, is still lacking. Most functional data concerns individual histone modifications that are easier to study. Nevertheless, it is thought that combinations of histone modifications may underlie a complex histone code, whereby each combination has a specific meaning in each context.⁶ Moreover, a higher level of complexity needs to be accounted for because, in addition to the four highly conserved core histones, eukaryotic organisms also produce smaller amounts of specialized variant histones that differ in amino acid sequence from the main ones, which can also assemble into nucleosomes and, consequently, affect the chromatin structure.³²,³³

In this context, a nomenclature to represent a specific histone modification was developed.³⁴ Briefly, the name of the histone (e.g., H3) is followed by the single-letter amino acid abbreviation (e.g., R for arginine) and the amino acid position in the protein (e.g., 17); then, the type of modification (me, methyl; p, phosphate; ac, acetyl; ub, ubiquitin) is indicated, followed by the number of modifications (e.g., 1, 2, or 3 for mono-, di-, or trimethylation, respectively). An example is H3R17me1,³⁴ which refers to monomethylation at arginine 17 of histone H3. This nomenclature allows a clear and unambiguous representation of specific histone modifications, and its knowledge is central to understanding the paragraphs that follow.

1.2: Alterations of histone modifications in human diseases

Increasing evidence has shown that aberrant profiles of histone posttranslational modifications are associated with a variety of human diseases, mainly because the dysregulation of these modifications alters the chromatin structure and induces abnormal gene expression. The altered profiles often result from dysregulation of histone-modifying enzymes, the key players underlying these changes.³⁵–³⁷ Indeed, mutations and cytogenetic alterations affecting genes encoding chromatin regulatory proteins are the main causes of pathogenic alterations in histone modifications.³⁸–⁴¹

Histone modification alterations are especially linked to cancer. Modifications of all four histones have been reported, although those affecting H3 and H4 are best understood, and acetylation and methylation are the most intensively studied histone marks affecting tumor development, disease progression, and response to therapy.⁴² Human tumors undergo a global loss of H4K16 acetylation and H4K20 trimethylation, which are considered epigenetic markers of malignant transformation.⁴³,⁴⁴ Interestingly, these alterations have been assigned to DNA repetitive regions that undergo DNA hypomethylation in cancer cells, another hallmark of malignant transformation,⁴³ posing the question of what takes place first. Regarding histone H3, the most studied residues that undergo methylation are lysines 9 and 27 (H3K9 and H3K27), which results in suppression of gene expression.⁴²,⁴⁵ Conversely, methylation of lysines 4 and 36 of the same histone (H3K4 and H3K36) promotes gene transcription.⁴²,⁴⁵ For example, alterations in H3K4 and H3K9 methylation are associated with several types of cancers⁴⁶ and result from disturbance in the balance between histone methyltransferases (HMTs, writers) and histone demethylases (HDMs, erasers). As expected, mutations and translocations affecting genes encoding chromatin regulatory proteins are some of the causes leading to this imbalance.³⁵–³⁷,⁴²

For example, among the various HMT enzymes, EZH2, NSD2, and DOT1L were shown to be highly expressed in tumors,⁴²,⁴⁶ and MLL is involved in chromosomal translocations with various partners, especially in leukemia.⁴²,⁴⁶

The lysine methyltransferase EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and mediates the mono-, di-, and trimethylation of lysine 27 of histone H3 (H3K27).⁴⁷ EZH2-catalyzed trimethylation of H3K27 induces the suppression of gene expression and high expression correlates with the onset and development of various types of cancer, including non-Hodgkin lymphomas and prostate cancer.³⁶,⁴⁸

NSD2 mediates dimethylation of H3K36, and it has been shown to primarily function as a transcriptional activator by increasing intragenic dimethylated H3K36 at active genes.⁴⁹,⁵⁰ For instance, NSD2 overexpression results from recurrent chromosomal translocation t(4; 14) in multiple myeloma (MM)⁵¹ or recurrent gain-of-function mutations in lymphoid malignancies.⁵²,⁵³

Chromosomal rearrangements at 11q23, which include the MLL gene (KMT2A, lysine methyltransferase 2A), are associated with acute leukemia.⁵⁴–⁵⁷ MLL is thought to function primarily as a transcriptional activator, at least in part through trimethylation of H3K4 at the promoters of active genes.⁴⁶ The HMT DOT1L, which was implicated in the development of MLL-rearranged acute myeloid leukemia (AML), catalyzes the methylation of H3K79.⁵⁸–⁶⁰ H3K79me3 is often observed at the transcriptional start sites of active genes and is believed to be important for efficient transcriptional elongation and active gene expression.⁶⁰

Histone demethylases (HDMs), the erasers of methylation, form another family of enzymes regulating histone methylation, which plays a role in tumor development.⁴⁶ LSD1 is a member of the FAD-dependent monooxidase family of enzymes and was the first HDM to be discovered. It catalyzes the demethylation of the mono- and dimethylated forms of H3K4 and H3K9.⁶¹,⁶² Increased LSD1 expression was reported in several cancers, including neuroblastoma,⁶³ prostate cancer,⁶⁴ colorectal and lung cancer,⁶⁵ and hematopoietic cancers such as myelodysplastic syndrome (MDS) and AML,⁶⁶ where it correlates with tumor onset and progression.

Loss of histone H3 acetylation at tumor suppressor genes is also observed in a variety of cancers, where it correlates with gene repression.⁶⁷ Moreover, H3K4 acetylation in breast cancer is associated with both early and late breast cancer cell phenotypes and is overrepresented at promoters of genes associated with estrogen response and epithelial-to-mesenchymal transition pathways.⁶⁸

Similarly to histone methylation, alterations in the histone acetylation status results usually from an imbalance between histone acetyltransferase (HATs, writers) and histone deacetylase (HDACs, erasers) activities.

Several HAT genes are altered by mutations, deletions, or translocations in various types of cancers, resulting in HAT enzyme dysregulation.⁶⁷,⁶⁹ HAT activity can also be dysregulated by viral oncoproteins.⁷⁰ HATs play an important role in oncogenesis by dysregulating not only the acetylation status of histones but also other nonhistone proteins.⁶⁷ For example, MOF, a member of the MYST family, which preferentially catalyzes acetylation of lysine 16 in H3 (H3K16), shows aberrant expression in some types of cancers, including breast cancer, medulloblastoma, ovarian cancer, and renal cell carcinoma.⁷¹ Conversely, decreased expression of Tip60 induces hypoacetylation of the p53 protein, thereby suppressing apoptotic signals and playing an antitumor role.⁴⁵,⁷² Mono-allelic loss of the Tip60 gene was observed in lymphomas, mammary carcinomas, and head and neck tumors.⁷²

In contrast to HATs, HDACs catalyze the removal of acetyl groups from lysine residues and promote gene repression. The dysregulation of HDACs has been extensively correlated with the occurrence of several cancers,⁷³,⁷⁴ such as neuroblastoma, lung and liver cancer, cutaneous T-cell lymphoma, and multiple myeloma, and, in most cases, high levels of HDACs are associated with advanced disease and poor outcome.⁷⁵–⁷⁹ In addition, these enzymes also deacetylate a large number of nonhistone proteins, which may be involved in the regulation of cell cycle, apoptosis, DNA-damage response, metastasis, and other cellular processes central to tumorigenesis.⁷⁴

Acetylated lysine residues in histones also provide a specific binding site for the bromodomain and extra-terminal (BET) family of proteins via their bromodomains. These proteins are considered readers of chromatin status and are able to recruit positive transcription elongation factors (pTEFb) and mediator complexes to chromatin.⁴²,⁸⁰ BET proteins have been reported to participate in the development of various cancers, including AML, MDS, lymphoma, multiple myeloma, and prostate and pancreatic cancers.⁸¹

In addition to the dysregulation of histone-modifying enzymes, nucleosome dynamics can be altered by mutations targeting residues that are subjected to posttranslational modifications or are in close proximity to them.⁸²–⁸⁴ For example, exon sequencing has identified K27M mutations in the H3F3A gene, a variant encoding histone H3.3, in pediatric glioblastomas, which lead to a global reduction in H3K27 trimethylation.⁸⁵

Also, in the context of cancer therapy, some recent studies have shown that, in addition to regulating the behavior of cancer cells, posttranslational modification of histones may also regulate immune response. In this regard, histone modifications were reported to influence the behavior of immune cells, such as dendritic cells (DCs), macrophages, cytotoxic T cells, NK cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), involved in the recognition and elimination of cancer cells.⁸⁶ Indeed, histone acetylation and methylation were shown to regulate the immune response by modulating the immunogenicity of cancer cells and affecting the expression of effector molecules and the differentiation and function of immune cells.⁶⁹ Therefore histone modification modulators in combination with immunotherapy should result in greater therapeutic efficacy. This hypothesis was corroborated by recent studies that have shown that immunotherapy in combination with HDAC inhibitors, and also HMT inhibitors or HDM inhibitors, although less commonly, is able to enhance immune response and overcome acquired resistance to immunotherapy.⁶⁹,⁸⁷–⁹¹

Besides what has been reported for cancer, the modulation of histone modifications is also common in diseases wherein the immune system has a central role, including infectious and autoimmune diseases.

Although less studied than cancer, a wide body of evidence has related pathogen infection with the alteration of histone marks in cells involved in the immune response triggered to neutralize them. Indeed, it is now recognized that infectious pathogens have the ability to shape gene expression in host cells for their own benefit, dampening host immune responses and potentiating their growth. Accordingly, some reports have shown that this can be achieved by inducing chromatin structure alterations through mechanisms such as histone posttranslational modifications.⁹²–¹⁰⁰ Briefly, following infection, bacterial components such as lipopolysaccharide (LPS) are sensed by immune cells, which promote an inflammatory response with the objective of eliminating the pathogen.¹⁰¹ However, for pathogenic bacteria to maintain a long-term presence, they develop mechanisms to limit the inflammatory response by silencing certain immunomodulatory genes through the alteration of histone marks.⁹²

Some studies have shown that bacteria target histone modifications on immune cells through effectors that can change signaling events involved in the recruitment or inhibition of host chromatin-modifying enzymes and/or factors that mimic them.⁹² For instance, Pseudomonas aeruginosa, a pathogen responsible for nosocomial infections, secretes 2-aminoacetophenone, which has antiinflammatory effects through increasing HDAC expression in monocytes and consequent deacetylation of histone H3K18 at promoters of inflammatory genes, including the tumor necrosis factor alpha (TNFα).¹⁰² As another example, the Rv1988 protein, which is secreted by pathogenic Mycobacterium tuberculosis, translocates to the nucleus, where it works as a methyltransferase, specifically targeting H3R42me2 in promoters of critical immune response genes, including NOX1, NOX4, and NOS2, and therefore repressing their transcription.¹⁰³

Most histone modifications studies in infectious diseases are related to bacteria, including Helicobacter pylori, which causes gastritis and stomach ulcers; Shigella flexneri, the etiologic agent of dysentery in humans; and Legionella pneumophila, which is the causative agent of Legionnaires’ disease (also known as legionellosis).⁹²,¹⁰⁴–¹⁰⁶ Additionally, there have also been reports regarding viruses (e.g., influenza virus, human immunodeficiency virus, and herpes simplex virus)⁹³–⁹⁶,¹⁰⁰,¹⁰⁶ and protozoans (e.g., Trichomonas vaginalis and Leishmania).⁹⁷,⁹⁹ Altogether, these studies uncover the potential of manipulating histone modifications to treat infectious diseases.

Autoimmune diseases are chronic inflammatory disorders characterized by the loss of immunological tolerance to self-antigens and the presence of autoantibodies, autoreactive T and B cells, and/or impaired suppressive function of regulatory T cells. Even though the pathogenesis remains largely unknown due to its inherent complexity, accumulating evidence has indicated a potential role for epigenetic mechanisms, including histone modifications, in the development of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and type 1 diabetes.⁴⁰ Hence, histone modifications in immune cells (e.g., B lymphocytes, monocytes, and T lymphocytes) may contribute to the dysregulation of immune response.⁴⁰,¹⁰⁷–¹¹⁰ The previous findings will most likely lead to the development of new epigenetic therapeutic strategies. Nevertheless, further studies are required to understand the function of several histone modifications implicated in the pathogenesis of autoimmune diseases.

Over the past two decades, the role of epigenetic mechanisms in the function and homeostasis of the central nervous system (CNS) has been unveiled. Moreover, several neurological disorders have been associated with long-term changes in gene expression related to chromatin structure alterations.¹¹¹ Indeed, the two most common neurodegenerative diseases, Alzheimer‘s disease and Parkinson's disease, have been shown to be affected by alterations in histone modifications,¹¹² and several HDAC, HMT, and HAT inhibitors are currently under clinical trials to treat these and other neurodegenerative diseases.¹¹³

Finally, although current knowledge regarding epigenetic mechanisms in cardiovascular diseases (CVDs) is still limited, preclinical studies in animal models have given some clues on the important role of histone posttranslational modifications in the pathogenesis of CVDs, which are the primary cause of death worldwide. Endothelial cell dysfunction and vascular smooth muscle cell dedifferentiation, proliferation, and migration are phenotypic changes characteristic of CVD manifestation and result from broad changes in gene expression. Supporting a role for histone modifications in regulating gene expression in CVD, inhibition of HDACs, HMTs, HDMs, or BET family of proteins were shown to prevent many of the cell phenotype changes associated with its pathogenesis.¹¹⁴–¹¹⁸ Specifically, histone methylation and histone acetylation in monocytes, macrophages, smooth muscle cells, and endothelial cells during atherosclerosis development have been reported.¹¹⁹,¹²⁰ Also, substantial evidence suggests HDACs as therapeutic targets for heart failure.¹²¹–¹²⁴

In addition, other conditions that are important cardiovascular risk factors, such as hypertension, diabetes, and obesity (especially visceral obesity and ectopic fat accumulation), are also affected by epigenetic alterations. Therefore targeting the mechanisms behind these alterations are currently considered as potential preventive and therapeutic approaches.

Hypertension results from complex interactions between genes and environmental factors, and recent evidence implicates posttranslational histone modifications, such as methylation, acetylation, and phosphorylation, in its development.¹²⁵–¹²⁷ Like other vascular pathologies, HDAC and BET inhibition tend to have similar beneficial effects on hypertension.¹²⁸,¹²⁹ Nevertheless, HDAC-mediated regulation of hypertension appears to depend on the experimental model used, as other authors did not find HDAC inhibitor-mediated effects on blood pressure.¹³⁰

The study of epigenetics in metabolic diseases is still a young research field. Nevertheless, a wide body of evidence suggests that when people with obesity and diabetes follow an unhealthy diet, it may affect their epigenome and thereby disease pathogenesis.¹³¹ Indeed, it is already known that disruption of histone modifications impacting on gene expression contributes to type 2 diabetes (T2D) and obesity.

T2D is characterized by chronically elevated blood glucose levels, which develop due to insulin resistance, for which aging, a sedentary lifestyle, and obesity are important contributing factors, in combination with impaired insulin secretion. Importantly, five million people die due to diabetes every year, most often because of cardiovascular incidents,¹³² and epigenetic changes in patients with diabetes may effectively contribute to vascular complications. Notably, there are some studies showing that HDACs regulate glucose homeostasis, pancreatic islet function, and inflammation.¹³³–¹³⁸ However, HDAC inhibition has been known to enhance insulin secretion, decrease inflammation, and improve insulin sensitivity.¹³⁹–¹⁴² Moreover, BET protein inhibition appears to promote insulin production and pancreatic beta cell differentiation.¹⁴³,¹⁴⁴

The potential role of epigenetic modifications in developing an obese phenotype was also unveiled. For example, when fed with the same high-fat diet, wild-type mice gained weight, became obese, and had reduced glucose tolerance with increased serum insulin, whereas HDAC3 knockout mice did not develop obesity and had less liver fat and smaller adipocytes.¹⁴⁵ Importantly, disruption of HDAC3 in intestinal epithelial cells of obese mice led to weight loss and improved the metabolic profile.¹⁴⁵ Another study has shown that quercitine and a derivative were able to prevent obesity in rats through the induction of repressive histone modifications leading to reduced expression of c/EBPα and PPARγ.¹⁴⁶ Therefore interfering with histone modifications is currently seen as a promising therapeutic strategy in both T2D and obesity.¹³¹

Importantly, the reversibility and accessibility of epigenetic modifications offer an opportunity to develop new strategies for the treatment of diseases.⁴² Therefore advances in our understanding of the roles of histone modifications and alterations will prompt the development of new targeted therapeutic strategies for a range of human diseases. Several of these epigenetic therapies are inclusively already in clinical use and even more are being evaluated in clinical trials.

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