FROM THE ACADEMY: COLLOQUIUM INTRODUCTION COLLOQUIUM INTRODUCTION Epigenetic changes in the developing brain: Effects on behavior Eric B. Kevernea, Donald W. Pfaffb, and Inna Tabanskyb,1 Indeed, epigenetics epitomizes the develop- aSub-Department of Animal Behaviour, University of Cambridge, Cambridge CB3 8AA, ment of the brain more than that of any other England; and bLaboratory of Neurobiology and Behaviour, The Rockefeller University, New structure. The billions of neurons exponen- York, NY 10021 tially magnified for function by the trillions of synaptic interconnections mean that no two brains are alike. Even monozygotic (MZ) This Sackler Colloquium encompasses a broad to an estrogen response element (7), followed twins show differences in behavior and in range of topics for the following reason. Our by the actions of coactivator proteins (8, 9). psychiatric disorders that become more marked knowledge of the chemistry of epigenetic Recent molecular endocrine papers are more with age (20). There are, as reported in this modifications is expanding at a rapid rate, ambiguous on the exact order of events (see Sackler Colloquium, reports of experience but most of the primary discoveries in this – Some Outstanding Questions,below)(10 12). driven heritable changes in the brain’s epi- field are made using nonneural tissue. So, The long-lasting epigenetic changes in the nu- genome, especially experiences involving ma- neuroscientists want to learn about this chem- clei of hypothalamic neurons, which are re- ternal care (13) and stress (21). Neural systems istry but may not have direct exposure to sponsible for the normal development of are designed to respond to the environment the material. In a complementary fashion, this chain of estrogen-dependent reproductive because the strengths of their synaptic con- molecular geneticists and protein chemists behaviors, have remained obscure. nections are activity-dependent. In humans who experiment on DNA methylation, histone Thus, the following series of papers in this the accumulation of brain knowledge across modifications, and noncoding RNAs realize Sackler Colloquium focus on mechanisms generations has played an integral role in that some of the most exciting applications of that include DNA methylation, genomic im- shaping and ameliorating environments to their discoveries are in the CNS, but for such printing, histone modifications, and noncod- optimize longevity and reproductive success. scientists behavioral assays, for example, are ing RNAs, applying this new knowledge to It is, however, important to distinguish distant from their expertise. The purpose of neuronal mechanisms for behavior, wherever between transgenerational hereditary and this Sackler Colloquium, therefore, was to possible.Hereweoffersubstantivebackgrounds intergenerational effects. Examples of the — bring together experts in the two fields on several types of mechanisms in play. latter include in utero exposure to nutritional epigenetic chemistry and behavioral neuro- To date, the behavioral systems most easily status, stress, or toxic environmental factors — science in the spirit of mutual education. explored with respect to epigenetic mecha- that act on the developing embryo and its We start with the chemistry of transcription nisms have been those that do not need to germ line (22). These intergenerational events itself. Decades of biochemical work led to the be learned. Thus, at the Sackler Colloquium should be distinguished from truly trans- concept of the basal transcriptional complex mechanisms discussed were those for ma- generational inheritance, which is found in (1, 2), and recently a structure for the tran- ternal behaviors (13), sexual behaviors and subsequent generations that were not exposed scription preinitiation complex was reported stress (14), and hypothalamically controlled to the initial environmental events that trig- (3). Neuroscientists concerned with the devel- behaviors (15). Circadian-regulated behav- gered the change. opment of behavior need to know the variety iors (16) clearly represent a case of normal When considering intergenerational effects of changes in the cell nucleus that precede the behaviors epigenetically regulated, whereas it is also important to consider which parent formation of that complex, with an emphasis problematic and abnormal behaviors, such as was exposed. Any harmful events experi- on those modifications that last a long time. in Prader-Willi syndrome (17), and changes enced in utero are likely to affect the next It has been established that specific genes in behavior during aging were also dis- generation of both males and females. These operating in specific neurons govern the cussed. Potential contributions of transposon events can also affect the third generation of appearance of specific, biologically crucial expression to expanded opportunities for neu- the female offspring, as the female germ line behaviors. The system that has been worked roplasticity were discussed at the meeting by develops in utero, where the primordial germ out in the most detail features estrogen- Gage, and are represented here among the cells undergo demethylation and remethyla- dependent female reproductive behavior (4, 5) Outstanding Questions emanating from tion. These epigenetic marks are likely to modulated by estrogen-facilitated transcription the meeting. of a range of genes in ventromedial hypo- This paper serves as an introduction to the articles which resulted thalamic neurons required to activate a spinal- Epigenetics from the Arthur M. Sackler Colloquium of the National Academy of midbrain-spinal circuit. Similarly, expression In 1946 Waddington (18) introduced the term Sciences, “Epigenetic Changes in the Developing Brain: Effects on of the gene encoding the estrogen receptor-α “epigenetics” to link the phenotype with ge- Behavior,” held March 28–29, 2014, at the National Academy of α Sciences in Washington, DC. The complete program and video re- (ER- ) in medial preoptic neurons is essential notype during development. The notion of cordings of most presentations are available on the NAS website at for the performance of maternal behaviors (6). heritability became linked to “memory” marks www.nasonline.org/Epigenetic_changes. For behavior and other physiological func- (DNA methylation) for propagating cell Author contributions: E.B.K., D.W.P., and I.T. wrote the paper. tions, early papers reported that the first mo- identity by structural regulation of chromatin The authors declare no conflict of interest. lecular event that leads to hormone-facilitated for gene-expression states (register, signal, or 1To whom correspondence should be addressed. Email: itabansky@ transcription, depends on the binding of ER-α perpetuate activity states) (19). rockefeller.edu. www.pnas.org/cgi/doi/10.1073/pnas.1501482112 PNAS Early Edition | 1of7 Downloaded by guest on September 23, 2021 persist in the egg, unlike those of the sperm, 5-hydroxymethylcytosine has been reported ceacams, and prolactins). These genes have which are erased after fertilization. In the ab- in Purkinje neurons (27). undergone multiple duplications across sence of in utero stressors or toxins, the mammalian species (Psgs 1–23, Ceas 1–19, demethylation/remethylation reprogramming Genomic Imprinting. During germ-cell de- Prls 3–18) with the lowest copy number in provides a major barrier to transgenerational velopment, genomic imprints are also estab- metatherians and highest in eutherian epigenetic inheritance. lished, allowing parent-of-origin specific ex- primates. An important feature of genes that In the context of intergenerational inheri- pression of particular genes. The primary are imprinted is their evolutionary stability tance, the placenta and brain are of particular origin and the role for the matriline in ge- through purifying selection, and the recruitment importance. The fetal placenta is integral to nomic imprinting (maternal methylation, of more genes to this epigenetic mode of the successful development of the next gen- maternal reprogramming) probably owes regulation (ICRs) has occurred across the eration, interacting and regulating much of much to its evolutionary significance and evolution of mammalian species (33). This maternal physiology and behavior, thereby success in mammalian in utero development. recruitment has often expanded the ICR to ensuring its own successful development and, Its contribution to placentation, metabolism, include noncoding RNAs. Imprinted gene in turn, that of its fetus continue. Maternal thermogenesis (body temperature regulation), clusters contain at least one long noncoding care interactions continue after birth, further maternal care, growth, and brain development RNA (lncRNA), and two clusters in partic- ensuring this next generation receives adequate are global functions targeted by imprinted ular (Kcnq1-Kcnq1 ot1; Igf2r-Airn)havean nutrition, warmth, and tactile stimulation. gene regulation. estimated 100 kb of lncRNA transcribed in Genomic imprinting is regulated by epi- an antisense direction from within the protein- DNA Methylation and Demethylation. In genetic marks in the imprint control region coding genes (34). The lncRNA plays an es- development, DNA methylation imposes a (ICR) of genes. These marks are heritable sential role in the imprinting of these clusters fundamental epigenetic barrier that guides and result in the monoallelic, parent of ori- and deletion of their promoter results in bial- and restricts developmental differentiation,