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Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 104-106-bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyper-acetylated CRDs were enriched for SCZ heritability, with prominent representation of regulatory sequences governing fetal development and glutamatergic neuron signaling. Therefore, SCZ and BD brains show coordinated dysregulation of risk-associated regulatory sequences assembled into kilobase- to megabase-scaling chromosomal domains.

Most risk variants for brain disorders identified by genome-wide association studies reside in the noncoding genome, which makes deciphering biological mechanisms difficult. A commonly used tool, multimarker analysis of genomic annotation (MAGMA), addresses this issue by aggregating single nucleotide polymorphism associations to nearest genes. Here we developed a platform, Hi-C-coupled MAGMA (H-MAGMA), that advances MAGMA by incorporating chromatin interaction profiles from human brain tissue across two developmental epochs and two brain cell types. By analyzing gene regulatory relationships in the disease-relevant tissue, H-MAGMA identified neurobiologically relevant target genes. We applied H-MAGMA to five psychiatric disorders and four neurodegenerative disorders to interrogate biological pathways, developmental windows and cell types implicated for each disorder. Psychiatric-disorder risk genes tended to be expressed during mid-gestation and in excitatory neurons, whereas neurodegenerative-disorder risk genes showed increasing expression over time and more diverse cell-type specificities. H-MAGMA adds to existing analytic frameworks to help identify the neurobiological principles of brain disorders.

Juvenile social isolation reduces sociability in adulthood, but the underlying neural circuit mechanisms are poorly understood. We found that, in male mice, 2 weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the posterior paraventricular thalamus (mPFC→pPVT) during social exposure in adulthood. Chemogenetic or optogenetic suppression of mPFC→pPVT activity in adulthood was sufficient to induce sociability deficits without affecting anxiety-related behaviors or preference toward rewarding food. Juvenile isolation led to both reduced excitability of mPFC→pPVT neurons and increased inhibitory input drive from low-threshold-spiking somatostatin interneurons in adulthood, suggesting a circuit mechanism underlying sociability deficits. Chemogenetic or optogenetic stimulation of mPFC→pPVT neurons in adulthood could rescue the sociability deficits caused by juvenile isolation. Our study identifies a pair of specific medial prefrontal cortex excitatory and inhibitory neuron populations required for sociability that are profoundly affected by juvenile social experience. Yamamuro et al. show that juvenile social isolation disrupts prefrontal neurons projecting to the paraventricular thalamus and associated prefrontal somatostatin interneurons, and thereby impairs sociability in adulthood.

Most risk variants for brain disorders identified by genome-wide association studies reside in the noncoding genome, which makes deciphering biological mechanisms difficult. A commonly used tool, multimarker analysis of genomic annotation (MAGMA), addresses this issue by aggregating single nucleotide polymorphism associations to nearest genes. Here we developed a platform, Hi-C-coupled MAGMA (H-MAGMA), that advances MAGMA by incorporating chromatin interaction profiles from human brain tissue across two developmental epochs and two brain cell types. By analyzing gene regulatory relationships in the disease-relevant tissue, H-MAGMA identified neurobiologically relevant target genes. We applied H-MAGMA to five psychiatric disorders and four neurodegenerative disorders to interrogate biological pathways, developmental windows and cell types implicated for each disorder. Psychiatric-disorder risk genes tended to be expressed during mid-gestation and in excitatory neurons, whereas neurodegenerative-disorder risk genes showed increasing expression over time and more diverse cell-type specificities. H-MAGMA adds to existing analytic frameworks to help identify the neurobiological principles of brain disorders.

Ibi, Daisuke et al., Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment., NIH R01 MH084894 (J.G.M.), NIH R01 MH111940 (J.G.M.), Dainippon Sumitomo Pharma (J.G.M.), NARSAD (J.G.M.), the Japan Society for the Promotion of Science (JSPS) 15H06719 and 16K19786 (D.I.), NIH R01 MH104491 (G.W.H.), NIH R01 MH086509 (S.A.), NIH P50 MH096890 (S.A.), MINECO/ERDF SAF2009-08460 (J.J.M. and L.F.C.), SAF2013-45084R (J.J.M. and L.F.C.), Basque Government IT616-13 (J.J.M.), NIH R21 MH103877 (S.D.) and NIH R01 MH090264 (S.J.R.) participated in the funding of this study. RNA-seq analysis was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai and the NIH infrastructure grant S10OD018522. C.M. and A.G.B. were recipients of a postdoctoral and a predoctoral fellowship from the Basque Government, respectively. D.I. was a recipient of postdoctoral fellowships from JSPS (Young Scientists JSPS 23-3454) and the Uehara Memorial Foundation.

Over the past decade, rapid advances in epigenomics research have extensively characterized critical roles for chromatin regulatory events during normal periods of eukaryotic cell development and plasticity, as well as part of aberrant processes implicated in human disease. Application of such approaches to studies of the CNS, however, is more recent. Here we provide a comprehensive overview of available tools for analyzing neuroepigenomics data, as well as a discussion of pending challenges specific to the field of neuroscience. Integration of numerous unbiased genome-wide and proteomic approaches will be necessary to fully understand the neuroepigenome and the extraordinarily complex nature of the human brain. This will be critical to the development of future diagnostic and therapeutic strategies aimed at alleviating the vast array of heterogeneous and genetically distinct disorders of the CNS.

Conclusive evidence for defective neurodevelopment in schizophrenia is lacking. Two DNA methylation studies now draw a link between fetal brain epigenomes, epigenetic alterations in the adult diseased brain and genetic risk for the disease.