Epigenetic Basis of Mental Illness

Abstract

Psychiatric disorders are complex multifactorial illnesses involving chronic alterations in neural circuit structure and function as well as likely abnormalities in glial cells. While genetic factors are important in the etiology of most mental disorders, the relatively high rates of discordance among identical twins, particularly for depression and other stress-related syndromes, clearly indicate the importance of additional mechanisms. Environmental factors such as stress are known to play a role in the onset of these illnesses. Exposure to such environmental insults induces stable changes in gene expression, neural circuit function, and ultimately behavior, and these maladaptations appear distinct between developmental versus adult exposures. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and the aberrant epigenetic regulation that underlies this dysregulation is a unifying theme in psychiatric disorders. Here, we provide a progress report of epigenetic studies of the three major psychiatric syndromes, depression, schizophrenia, and bipolar disorder. We review the literature derived from animal models of these disorders as well as from studies of postmortem brain tissue from human patients. While epigenetic studies of mental illness remain at early stages, understanding how environmental factors recruit the epigenetic machinery within specific brain regions to cause lasting changes in disease susceptibility and pathophysiology is revealing new insight into the etiology and treatment of these conditions.

Keywords: 3D chromatin structure; DNA methylation; bipolar disorder; depression; histone acetylation; histone methylation; microRNA; schizophrenia.

Figure 1

Scheme of posttranslational modifications of histones. (A) The nucleosome is the functional unit of chromatin, composed of 147 bp of DNA wrapped around a core octamer of histone proteins (two copies each of H2A, H2B, H3, and H4). The N-terminal tails of these histones face outward from the nucleosome. (B) Combinations of acetylation, phosphorylation, methylation, and so on, on histone tails (here, H3 is depicted) alter chromatin compaction and regulate gene expression. Histone modifications that weaken the interaction between histones and DNA or that promote the recruitment of transcriptional activating complexes (e.g., H3 acetylation at K23, K18, K14, and K9, as well as methylation at K79, K36, and K4 or phosphorylation at S28 and S10) correlate with permissive gene expression. Histone deacetylation, which strengthens histone–DNA contacts, or histone methylation on K27 or K9, which recruits repressive complexes to chromatin, promote a state of transcriptional repression. Adapted from Tsankova and others (2007) (permission not required).

Figure 2

Epigenetic regulation in brain. Left: In eukaryotic cells, DNA wraps around histone octomers to form nucleosomes, which are then further organized and condensed to form chromosomes. Unraveling compacted chromatin makes the DNA of a specific gene accessible to the transcriptional machinery. Right: Stress and other environmental stimuli act in large part by altering synaptic function to alter intracellular signaling cascades, which leads to the activation or inhibition of transcription factors and of many other nuclear proteins; the detailed mechanisms involved in the latter remain poorly understood. This leads to the induction or repression of particular genes, including those for noncoding RNAs; altered expression of some of these genes can in turn further regulate gene transcription. It is hypothesized that some of these changes at the chromatin level are extremely stable and thereby underlie lifelong susceptibility to mental illness. CREB = cAMP response element binding protein; DNMTs = DNA methyltransferases; HATs = histone acetyltransferases; HDACs = histone deacetylases; HDMs = histone demethylases; HMTs = histone methyltransferases; MEF2 = myocyte enhancing factor-2; NFκB = nuclear factor κB; pol II = RNA polymerase II. From Robison and Nestler (2011) (permission not required).

Figure 3

Examples of chromatin modifications regulated by stress or antidepressant treatment. Illustration (top) indicates histone octamers (pink) in heterochromatin (left) and euchromatin (right), along with associated proteins and histone tail/DNA modifications. Table (bottom) lists histone tail modifications of specific residues—depicted on the expanded histone tail illustration (left)—that are regulated by various stress paradigms or antidepressant treatments within the indicated brain regions. Arrows indicate an increase (green) or decrease (blue) in specific modifications. A = acetylation; P = phosphorylation; M (in a square) = histone methylation; M (in a circle) = DNA methylation; AMY = amygdala; HAT = histone acetyltransferase; HDAC = histone deacetylase; HPC = hippocampus; HMT = histone methyltransferase; HR and LR = high responding and low responding, respectively (with respect to baseline locomotor activity); pol II =RNA polymerase II. Modified from Peña and others (2014) with permission.

Figure 4

Hypothesized role of chromatin remodeling ACF complex in NAc in stress susceptibility. Chronic social defeat stress CSDS, via increased burst firing of VTA neurons and BDNF release, induces ACF1 expression in NAc. The resulting upregulation of ACF complex activity, possibly through changes in TSS (transcription start site) nucleosome positioning, represses a set of genes in NAc, the reduced expression of which contributes to susceptibility. Blurry nucleosomes in the right figure represent weakly positioned or delocalized nucleosomes at TSSs. From Sun and others (2015) (permission not required).

Figure 5

Higher order chromatin structure and schizophrenia. The role of higher order chromatin structure in transcriptional regulation of SCZ relevant genes has been shown for GAD1 (A) and CACNA1C (B). (A) GAD1, encoding GABA synthesis enzyme, is located on chromosome 2 (Ch2) and frequently down-regulated in cerebral cortex of SCZ patients (dashed black arrow) and this is associated with lower levels of active histone marks, including H3K4me3 (blue square) at the GAD1 transcription start site (TSS). The TSS region of GAD1 has been shown to physically interact with an AP1 motif-enriched enhancer region located 50 kb further upstream (also enriched in H3K4me3 mark, blue square). Evidence has been presented that a chromatin loop (red arrow), that may carry a cargo such as AP1 transcription factors (purple oval) into close proximity to the core promoter region facilitating GAD1 gene transcription, is weakened in brains of SCZ patients brain (dashed red arrow). This could contribute to lower GAD1 expression. (B) Several single nucleotide polymorphisms (SNPs) residing in noncoding regions of the CACNA1C gene on chromosome 12 (Ch12) have been associated with lower CACNA1C expression and SCZ risk. The rs215100 T SCZ risk allele (green bar) resides in an intronic enhancer region, 185 kb downstream from the CACNA1C TSS, which has been shown to physically interact with the CACNA1C TSS (solid red arrow). The T allele confers lower transcriptional activity (dashed black arrow) as compared to C allele (solid black arrow), presumably by affecting the binding of transcription factors (TF, purple oval) and their interaction via chromosomal loops with the promoter CACNA1C region.