Behavioral epigenetics

Abstract

Sponsored by the New York Academy of Sciences, the Warren Alpert Medical School of Brown University and the University of Massachusetts Boston, "Behavioral Epigenetics" was held on October 29-30, 2010 at the University of Massachusetts Boston Campus Center, Boston, Massachusetts. This meeting featured speakers and panel discussions exploring the emerging field of behavioral epigenetics, from basic biochemical and cellular mechanisms to the epigenetic modulation of normative development, developmental disorders, and psychopathology. This report provides an overview of the research presented by leading scientists and lively discussion about the future of investigation at the behavioral epigenetic level.

Figure 1

The figure shows the 96 articles on behavioral epigenetics grouped by the behavioral construct studied and the genes that were studied in each of the behavioral construct categories.

Figure 2

General scheme of chromatin remodeling. (A) DNA double helix wrapped around an octomer of histone proteins forming the unit of chromatin, the nucleosome. (B) Chromatin can be conceptualized as existing in two primary structural states: as active, or open, euchromatin in which histone acetylation opens up the nucleosome to allow binding of the basal transcriptional complex and other activators of transcription; or as inactive, or condensed, heterochromatin, where all gene activity is permanently silenced. In reality, chromatin exists in a continuum of several functional states (active, permissive, repressed, and inactivated). Enrichment of histone modifications, such as acetylation (A) and methylation (M) at histone N-terminal tails and related binding of coactivators (Co-Act) or repressors (Rep), to chromatin modulates the transcriptional state of the nucleosome.

Figure 3

The timescales of human adaptability. Light gray, more rapidly responsive/less durable; black, slowest to respond/most durable. Epigenetic changes contribute to multiple modes of adaptation, including developmental and intergenerational processes that allow adjustment to gradual environmental change occurring on a decadal or multigenerational timescale. Modified after Kuzawa’s work.

Figure 4

Schematic representation of epigenetic modifications. (A) In the nucleus, DNA coils and condenses around histones. Each octameric histone core contains two copies each of histones H2A, H2B, H3, and H4. The DNA-protein complex is referred to as chromatin. (B) The DNA-histone interaction occurs at the N-terminal tail of a histone, where, for example, on the H3 N-terminal tail, there are several sites for epigenetic marking via acetylation, methylation, and phosphorylation. (C) In and around gene promoters that are rich in cytosine-guanine nucleotides (CpG islands), methyl groups are transferred to CpG sites. This process, called DNA methylation, is catalyzed by a class of enzymes known as DNA methyltransferases.

Figure 5

HDAC3 modulates memory formation in a Nr4a2-dependent manner. (A) HDAC3-FLOX mice with dorsal hippocampal deletion of Hdac3 exhibit significantly enhanced long-term memory as compared to wild-type littermates (both groups received RISC free control). In contrast, siRNA-Nr4a2–treated HDAC3-FLOX mice exhibit no enhanced memory. (B) qRT-PCR shows that siRNA against Nr4a2 significantly reduces Nr4a2 expression in both HDAC3-FLOX and wild-type littermates.

Figure 6

Glucocorticoid hormones, secreted as a result of a stressful event, enhance the consolidation of behavioral responses, including memories related to the event. Until recently, the underlying mechanisms of these effects were unknown. Recent work of the Reul group at the University of Bristol shows that glucocorticoids act by binding to glucocorticoid receptors (GRs) that interact with the NMDA receptor-activated ERK1/2/MSK1-Elk-1 signaling pathway enhancing the formation of epigenetic modifications (i.e., the serine10 phosphorylation and lysine14 acetylation in histone H3 (H3S10p-K14ac)) and the induction of the neuroplasticity-associated immediate-early genes c-Fos and Egr-1 in sparsely distributed mature dentate gyrus neurons. Evidence has been accumulating that these signaling, epigenetic, and genomic phenomena are of critical importance for the consolidation of memories related to the endured stressful event.

Figure 7

Association between greater than median glucocorticoid receptor exon 1_F methylation and infant attention score is specific to nongrowth restricted infants.

Figure 8

Epigenetic mechanisms underlying persistent alterations on promoters of genes involved in neuronal plasticity.

Figure 9

Tactile stimulation derived from pup LG increases 5-HT activity at the level of the hippocampus, thus increasing NGFI-A expression and its association with the exon 1₇ promoter, which then initiates an alteration of the methylation state of the exon 1₇ glucocorticoid receptor promoter.

Figure 10

Mechanism of increased cocaine sensitivity.