Developmental Human Behavioral Epigenetics: Principles, Methods, Evidence, and Future Directions

Developmental Human Behavioral Epigenetics: Principles, Methods, Evidence, and Future Directions, Volume 23, a new volume in the Translational Epigenetics series, offers the first systematic account of theoretical G79 frameworks, methodological approaches, findings, and future directions in the field of human behavioral epigenetics. Featuring contributions from leading scientists and international researchers, this book provides a comprehensive overview of human behavioral epigenetics, with a close examination of evidence gathered to-date from animal models, challenges of human-based research and clinical translation, pathways towards drug discovery, and next steps in research.

Areas of focus include prenatal stress exposures, preterm behavioral epigenetics, intergenerational exposures, trauma and neglect, socio-economic conditions, maternal caregiving and attachment, study design, and epigenetics and psychotherapy.

• Enables more effective study design and methods application in behavioral epigenetics research across human and animal models
• Examines findings in human behavioral epigenetics to-date
• Features contributions from leading international researchers in behavioral epigenetics

• Language: English
• Publisher: Academic Press
• Release date: Nov 12, 2020
• ISBN: 9780128192634

Book preview

Developmental Human Behavioral Epigenetics

Principles, Methods, Evidence, and Future Directions

First Edition

Series Editor

Trygve Tollefsbol

Comprehensive Cancer Center, Comprehensive Center for Healthy Aging, University of Alabama at Birmingham, AL, USA

Livio Provenzi

Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy

Rosario Montirosso

0-3 Center for the at-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy

Table of Contents

Cover image

Title page

Copyright

Contributors

Keeping complexity in mind

Section I: Introduction

Chapter 1: Principles of epigenetics and DNA methylation

Abstract

Definition of epigenetics

Types of epigenetic modifications

Environmental effects, cell metabolism and epigenetics

Methods for methylation analysis

Single-cell epigenomics

Chapter 2: From animal to human epigenetics

Abstract

A rat story: Behavioral epigenetics beginnings

Post-natal maternal environment shapes the epigenome and adult behavioral phenotypes of the offspring

Environmental stimuli delivered to parents trigger processes to transmit information to offspring

Permissive environments

Aversive environments

Epigenetic perturbation can be passed along

Combining human and non-human animal research

Chapter 3: An overview of developmental behavioral genetics

Abstract

Background/history

Behavioral genetic methodology

Key interpretative issues

Key results from twin and adoption studies

Genomic approaches to behavioral genetics

Concluding remarks

Section II: Behavioral epigenetics in action

Chapter 4: Prenatal exposures and behavioral epigenetics in human infants and children

Abstract

Early environmental programming

Biological embedding

Fetal DNA methylation after exposure to prenatal stress

Does DNA methylation at birth predict postnatal outcomes?

Further directions

Chapter 5: Applying behavioral epigenetic principles to preterm birth and early stress exposure

Abstract

Introduction

Background

State of the art of PBE research

Future directions

Clinical implications

Chapter 6: Long-term epigenetic effects of parental caregiving

Abstract

The special case of human parenting in the ELA spectrum

Gene- (parenting-)environment interactions and epigenetics

Parental care and offspring DNA methylation

Epigenetics and attachment theory

Challenges and opportunities for epigenetic studies on parenting

Outlook

Chapter 7: Intergenerational transmission of stress-related epigenetic regulation

Abstract

A brief history of inheritance of acquired characteristics

Epigenetic mechanisms

Intergenerational, transgenerational inheritance of stress in humans and animals

Mechanisms of epigenetic inheritance

Future directions, conclusions

Chapter 8: The role of protective caregiving in epigenetic regulation in human infants

Abstract

Introduction

Maternal caregiving and DNA methylation

Future perspectives

Conclusions

Chapter 9: Embedding early experiences into brain function: Perspectives from behavioral epigenetics

Abstract

Acknowledgments

Perspectives

Index

Copyright

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Contributors

Chloe Austerberry     University College London, London, United Kingdom

Erica Berretta     IRCCS Santa Lucia Foundation, Rome, Italy

Andrée-Anne Bouvette-Turcot

Department of Psychology, McGill University

Batshaw Youth and Family Center, Montréal, QC, Canada

Francesca Cirulli     Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy

Nicholas Collins     Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, United States

Debora Cutuli     IRCCS Santa Lucia Foundation, Rome, Italy

Lourdes Fañanás

Department of Evolutionary Biology, Ecology and Environmental Sciences, Faculty of Biology, University of Barcelona, Barcelona

Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Madrid, Spain

Pasco Fearon     University College London, London, United Kingdom

Roberto Giorda     Scientific Institute IRCCS ‘‘E. Medea", Molecular Biology Laboratory, Bosisio Parini, LC, Italy

Elena Guida     0-3 Center for the at-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy

Shantala A. Hari Dass     National Centre for Biological Sciences – Tata Institute of Fundamental Research, Bangalore, India

Richard Hunter

Developmental Brain Sciences Program

Department of Psychology, University of Massachusetts Boston, Boston, MA, United States

Daniela Laricchiuta     IRCCS Santa Lucia Foundation, Rome, Italy

Eleonora Mascheroni     0-3 Center for the at-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy

Maria Meier     Department of Psychology, Division of Clinical Neuropsychology, University of Constance, Constance, Germany

Rosario Montirosso     0-3 Center for the at-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy

Helena Palma-Gudiel

Department of Evolutionary Biology, Ecology and Environmental Sciences, Faculty of Biology, University of Barcelona, Barcelona

Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Madrid, Spain

Laura Petrosini     IRCCS Santa Lucia Foundation, Rome, Italy

Livio Provenzi     Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy

Tania L. Roth     Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, United States

Ed Tronick

Developmental Brain Sciences Program

Department of Psychology, University of Massachusetts Boston, Boston, MA, United States

Eva Unternaehrer

Department of Psychology, Division of Clinical Neuropsychology, University of Constance, Constance, Germany

Child and Adolescent Research Department, Psychiatric University Hospitals Basel (UPK), Basel, Switzerland

Keeping complexity in mind

Ed Tronick; Richard Hunter, Developmental Brain Sciences Program, University of Massachusetts Boston, Boston, MA, United States, Department of Psychology, University of Massachusetts Boston, Boston, MA, United States

Prologue for Livio Provenzi & Rosario Montirosso (eds.)

Developmental Human Behavioral Epigenetics, ELSEVIER, San Diego

It is thrilling to see what we are discovering about molecular epigenetics. The research presented in this volume is fundamental. It is exciting to be able to examine the molecular epigenetics of the interaction of genes and environment leading to the behavioral phenotype. It is an instantiated reality that earlier developmental biologists could only dream about. Take a moment to realize that we are integrating molecular genetic processes and micro- and macro-environmental stimuli into a characterization of how an organism functions in the world; its behavioral phenotype. It is breathtaking. That said, borrowing a phrase from politics, that enthusiasm can be hard to maintain in the face of nuance and cautions, we want to introduce some significant caveats to the state of the field while struggling to maintain the excitement of discovery. We hope not to dim our enthusiasm. Rather, we want to introduce some cautions that actually present critical new challenges that have emerged because of our success. As we overcome them, the field will move forward. Additionally, we suggest a conceptual model, the buffer-transducer model (BTM). It is a model we are enthusiastic about. It situates molecular epigenetics in a dynamic and complex view of the forces and developmental processes operating to produce the phenotype. Our goal is not to convince you that the BTM is correct (though, of course it is!). We present it here as an illustration of the kind of complex thinking we need to engage in to understand epigenetic effects in a larger developmental context.

Certainly, we need to search always for a better way to do our research, but we do not know what that better way is, although it certainly is not a singular way. Part of what we are calling for is a more humble stance in relation to how we talk about and conceptualize epigenetic processes. It is a way of speaking that does not focus on making epigenetics preeminent and singularly sovereign in generating the phenotype. Indeed, epigenetic mechanisms have always been conceptually embedded between genotype and environment. It is a way of speaking—thinking—that fully recognizes the complexity of what we are trying to understand and a way that constantly reminds of us of what we do not know. Thus while to go about our work simplification may be—actually is—necessary, our conceptualizations and our operationalizations have to keep the complexity in mind so that we will not miss things and will increase the likelihood that we will grapple with and uncover the phenomenon of significance.

Briefly, let us suggest some caution in our thinking about molecular epigenetics, ideas developed more fully elsewhere (Lester et al., 2011; Tronick & Hunter, 2016). Our view is that there are a host of biological, physiological, nervous system and brain systems, and psychological and environmental factors that dynamically interact over time shaping the phenotype. Moreover, the phenotype in and of itself affects the interplay of these factors and itself. Complicated! A functional view of epigenetics might see it as a mechanism for quick adaptation by the organism (as opposed to the species) to the environment. But even this simple definition requires caution. Quick is undefined and its metric (seconds, hours, days, or even years) is likely to change depending on the factors involved and the context. Moreover, other mechanisms, such as learning, may serve the same function and be indistinguishable from an epigenetic change (e.g., Miller & Sweatt, 2007). Thus, the extent to which molecular mechanisms are, or are not, involved has to be determined, and more than one process may be simultaneously operating to produce a particular outcome. Furthermore, the organism’s preference for using one or another mechanism or a combination of mechanisms remains unstudied. In infants for example, leaning to avert gaze from a stressor is likely to utilize less biological capital than engaging genetic mechanisms for adapting to the stress, but is it preferentially employed? In what circumstances?

We are vague about when we use the term adaptation. The term is invoked most often when genes are involved, which already is a problematic use of the term since the adaptation referred to is often not more than a speculation, a just so story. What do we mean by adaptation when we are talking about epigenetic processes? Certainly some of them are not adaptive in an evolutionary sense, a sense of the term which we seldom examine empirically. Those problems aside, what changes are adaptive in the short run? One need only to consider the myriad of epigenetic changes in psychopathologies to recognize that many changes are unlikely to be adaptive in any obvious sense, particularly when the context that created them is less well defined than the molecular marks we are tempted to give our whole attention to.

A similar vagueness in conceptualization of our actual empirical research—the hands-on work—characterizes the description of the terms environment or context. Their vagueness may be even more concerning than that for adaptation. To say that the environment is typically undercharacterized is to grossly undercharacterize its description, especially while studying epigenetic processes. After all the brilliance of epigenetics is its integration of molecular processes and environmental events. While the molecular work is stunningly elegant, the work on the environment is crude. In many studies, a standard protocol or procedure may be utilized, but its details are unspecified. For example, a rodent behavioral task might not control for or report light levels, despite this simple, easily reportable environmental factor’s long-documented effects on behavior. With that example in mind, it takes little effort to see how much more complex factors, such as life history, might be underreported or inadequately described. Nevertheless, it is these sorts of contextual details that are thought to be responsible for generating molecular epigenetic changes. Licking rat pups by the dam does not capture what is going on, such as how many licks, how hard, how long, and in what context (home cage or open space) and portion of a diurnal cycle. Yet for any invocation of epigenetic processes, these details matter; they are half of any epigenetic formulation. They are the "whats" that make for epigenetic changes. Specifying them is needed, and demanded.

Furthermore, to highlight one of the unspecified whats is the near total lack of concern for the state of the organism. In what state—distress, sleep, wakefulness, or hunger—is the pup? Does licking really have the same effect on a sleeping pup as it would on the one in distress, on a pup that is nursing or alert? Indeed, developmental psychologists know that state changes how an organism (human infant) reacts to the same stimulus. Neuroendocrinologists recognize that internal states dictate complex, state-dependent changes in physiology that can both encode epigenetic changes and be influenced by previous experience. Thus, the organismic state along with the stimulus/context needs careful specification.

A way to put this issue is that the environmental phenotype is indeterminate; it is underspecified. The very fact that we do not have a specific term of art for environmental phenotype is a mark of our conceptual blind spot in this regard. However, it is not even that simple. There are issues related to the time frame. After the experimental procedure is completed, the organism is put into a totally different—which we also leave unspecified and unobserved—environment. But back to time. In different studies, time periods vary wildly. Yet again, from an epigenetic framework, we must believe that those unobserved whats over those varying time periods lead to epigenetic changes. Epigenetic changes are not suspended just because those periods of time away from the experimental procedure are not the researchers’ focus. Furthermore, there are two other related issues of concern about time. A counterargument to the issue of time is that the experimental and controls are put into the same environment for the same amount of time and so they have the same exposure. This argument ignores the fact that the organisms are not the same. One organism has had a change induced by the experimental condition; its conspecific has not. As such, they will react to the environment in different ways and likely come out of it with different epigenetic changes induced by the environment. Second, making matters even more indeterminate is that in many studies, these out-of-sight time periods are long enough that they go over developmental transitions and sensitive periods. Thus again, the organism that is brought back for evaluation is not the organism that was initially studied. They have changed in ways related to development, and developmental changes are most often qualitative. A significant way they have changed is that how and which epigenetic changes occur in each of them may now be different than the way the changes occurred earlier when each was in the same but different state of developmental organization. A start to come at these issues of duration of exposures and developmental transitions would be to do time courses and dose-response studies for environmental factors as one does in pharmacology. However, complexity is added by the need to include specification of life history, biological sex, and social arrangements intersecting with the temporal factors—not easy, but at least a conceptually tractable one.

Underlying these issues is another, perhaps insidious issue. The concept is that the initially induced epigenetic change is stable—fixed. The belief leads to a number of false conclusions, which fly in the face of how we think about epigenetic changes and developmental processes. One is that the epigenetic change does not have any additional effect once it has occurred. Such a view is simply, well, silly. Even if the particular change is fixed and unchanging for one system, it has epigenetic effects and other kinds of effects on other systems. Another issue is what accounts for the stability. Outside of cell biology and biochemistry, typically the view is that the change is in and of itself fixed and stable. An alternative is that stability is maintained and perhaps even created anew by the ongoing environment. Epigenetic changes induced by stress may be maintained by the organism remaining in a stressful environment. They may also be maintained by a change in the organization of the organism that was generated by the epigenetic change initially induced by the stressor. For example, an individual experiencing a trauma that induces epigenetic changes in their cortisol receptors may maintain the change, even amplify it because their physiology now is in and of itself is stressing. A more radical perspective is that a stable epigenetic change is actually created and re-created anew by the ongoing environment and/or by organismic changes. Indeed, this view is more in line with the actual behavior of molecular epigenetic marks than the received view: most molecular epigenetic marks are maintained by a balance of writer and eraser enzymes acting in concert. The metaphor of a printed mark is misleading, the letters of the codes of life are not written on paper but on water. Epigenetics is fundamentally dynamic in nature and reflects the constant interplay between the organism and the environment across multiple time scales.

Much of what we know about epigenetic changes, especially in humans, is from studies of models of abnormal processes, such as toxic exposures, deprivation, or experimental paradigms. These studies are, without doubt, revealing, but they may not characterize the typical operation of epigenetic processes. From the perspective of a dynamic system, while some animals exist in what may be thought of as outlier locales in the species’ typical state space, how they are functioning may not characterize the operation of their more typical conspecifics. They are almost by definition atypical. Thus, they may be poor models of typical processes, but critically, we can only know what is typical if we know what the typical processes look like. And looping back the typical is only typical in particular environments.

This issue is particularly acute with regard to work on the behavior of laboratory animals, which are customarily kept in environments that deviate so profoundly from their natural contexts so as to be—in some cases, frankly—pathogenic, and they are our controls. Furthermore, there is an emphasis on adverse events or trauma in our studies of epigenetic changes. However, the induction of changes is more than likely related to quotidian processes rather than extreme events. Certainly, extreme events can generate epigenetic changes, but it is unlikely that those changes are related to the processes of epigenetic changes induced by variations in typical species-specific events, such as caretaking (DiCorcia & Tronick, 2011).

We utilize the two models (see Figs. 1 and 2) to guide our work on humans and animals—neither is meant to be definitive. They are simply illustrative of the complexity of the phenomenon we are trying to understand. Fig. 1 presents the buffer-transducer model (BTM), and Fig. 2 presents its operation over time. Even in its complexity, the reader needs to be cognizant that both are simplifications. Here, we focus on its application to humans. The BTM operates on the microtemporal process of the continuous and ongoing engagement of the organism and the environment for gaining resources for the maintenance of its organization and for its growth and development. The BTM conceptualizes the caretaker-infant mutual engagement as a system for regulating the infant’s acquisition of resources, energy, and information, as a final common pathway either buffering or transducing the effects of different factors or events that affect the organism, resulting in its behavioral phenotype. As such, with the centrality of the caretaker-offspring pathway, the BTM is more likely appropriate for altricial animals, such as humans. Though the different factors in the model and the outcomes (see Fig. 1) are from different domains - such as physiology, psychology, sociology, epigenetics - all of them are considered either resource-depleting or resource-enhancing factors. Over time, they all interact and affect the phenotype. They are environmental, cultural, genetic, epigenetic, physiological, psychological, and relational or regulatory. Their interactions result in the quality of the organisms’ outcome. And even that outcome, be it good or bad, acts as a depleting or enhancing factor as it interplays with the other factors.

Fig. 1 The buffer-transducer model: All the factors in the model dynamically interact to affect the development of the phenotype.

Fig. 2 Ongoing outcomes become causal. Effects of resource enhancing and depleting factors accumulate, cascade, and over time become causal.

In a cascade of resource depletion, for instance, low maternal education (e.g., less than high school) and associated factors (e.g., poverty) deplete resources because such mothers are likely to have poorer self- and infant-regulatory capacities, leading to a stressed infant. Epigenetic changes are induced in the glucocorticoid receptor, and the immune system is weakened. Other physiologic systems become dysregulated or distorted. As a consequence, the infant’s health and behavior are compromised, and in turn it becomes more difficult for the caretaker to manage the infant. These consequential outcomes across multiple systems become causal, such that there is self-amplification. The cascade leads to further compromise of the phenotype, increasing derangement of its organismic systems and even of its environment. What is most important to see is that what unites these different components into a dynamic complex system is the interplay of different components over time and the central role of the infant–caretaker dyad resource regulating system. It is also worth noting that what we describe here can also be conceptualized as a process of adaptation to an adverse environment, which, in turn, calls on us to attend to the fact that adaptation and socially or personally desirable outcomes are not the same thing. Furthermore, it calls us to the fact that the outcomes we are studying here, whether molecular or sociodemographic, are affected by the structure of the environment, which is poorly specified and the organism’s engagement with it.

It should be clear that these dynamic models are far more complex and demanding than could be enacted in a single study or even a host of studies. Certainly, we have not done it even in our own studies, in which we have looked at epigenetic changes in relation to caretaking and other factors longitudinally. At best, in any study, we only gain traction on some components and processes of the models, and it is already simplified. However, the reason for presenting the model is for it to serve as a cautionary note. While the epigenetic studies in this volume are formidable, we must not let them lead us into simplified thinking. Simplification is necessary, but so is keeping the dynamic complexity in mind, which will make it far more likely that we will grapple with and uncover a phenomenon of significance. While being thrilled with what we are finding out about molecular epigenetics, we need to remove our blinkers, or at least acknowledge we are wearing them. One of the vistas those blinkers were blocking is our view of the environment as a part of the dynamic structure of the organism itself. This realization calls us to reach higher and take more time to think about and study environmental factors as elements of organismal development, particularly how environments interact with each other and with the organism over time. We recognize that we cannot do complete empirical justice to the dynamic nature of the systems we are studying. But what we can do is keep them in mind and speak of their complexity and limitations, even if it is to only remind ourselves of the unstudied complexity, as well as the complexity we could study, but have thus far set aside.

References

DiCorcia J., Tronick E. Quotidian resilience: Exploring mechanisms that drive resilience from a perspective of everyday stress and coping. Neuroscience and Biobehavioral Reviews. 2011;35:1593–1602.

Lester B., Tronick E., Nestler E., Abel T., Kosofsky B., Kuzawa C.,… Wood M. Behavioral epigenetics. Annals of the New York Academy of Sciences. 2011;1226:14–33.

Miller C.A., Sweatt J.D. Covalent modification of DNA regulates memory formation. Neuron. 2007;53:857–869.

Tronick E., Hunter R.G. Waddington, dynamic systems, and epigenetics. Frontiers in Behavioral Neuroscience. 2016;10:107. doi:10.3389/fnbeh.2016.00107.

Section I

Introduction

Chapter 1: Principles of epigenetics and DNA methylation

Roberto Giorda    Scientific Institute IRCCS ‘‘E. Medea", Molecular Biology Laboratory, Bosisio Parini, LC, Italy

Abstract

The term epigenetics originally denoted the processes by which a fertilized zygote developed into a mature, complex organism. The definition was eventually modified to focus on ways in which heritable traits can be associated not with changes in nucleotide sequence, but with chemical modifications of DNA, or of the structural and regulatory proteins bound to it. Metabolic changes and environmental stimuli can affect epigenetic regulation and influence the predisposition to a variety of diseases. A large number of techniques have been devised to study epigenetic marks, and DNA methylation in particular. In particular, new innovative approaches