The exploration of brain epigenomes, including DNA methylation and covalent histone modifications, has provided fundamentally new insights into the mechanisms of brain ontogenesis and maturation. Moreover, deleterious mutations and rare structural variants in more than 50 genes encoding various types of chromatin regulators have been linked to neurodevelopmental diseases, including autism spectrum disorders (ASDs). Therefore, it is now generally accepted that proper regulation of chromatin structure and function during pre- and early postnatal development is critically important for the proper unfolding of cognitive abilities and emotional states. ASDs are a group of neurodevelopmental conditions bound together by broad syndromic overlap, with key behavioral deficits in social interaction, communication, and motor behavior including stereotypies. There is a strong genetic contribution to ASDs, yet environmental influences may also be etiologically important. Only a few studies, however, studied chromatin structures in diseased tissue (i.e., postmortem brain tissues from ASD subjects). In addition, epigenetic regulations, including histone modification landscapes, are highly specific for cell type, which is a key challenge for the field given the enormous cellular heterogeneity of the brain tissue, with multiple sub-population of inhibitory and excitatory neurons and various types of non-neuronal cells residing in the same tissue blocks. In this exploratory proposal, we will develop and test radically novel approaches in the human brain research, including the sorting of multiple subtypes of cortical neurons and the cell type-specific charting of 3- dimensional chromosomal architectures at selected genomic loci, with focus on ASDs. Specifically, we will profile open chromatin-associated histone methylation and acetylation, and promoter-enhancer associated chromosomal loop formations in GABAergic interneurons derived from the medial ganglionic eminence (MGE), in comparison to other neurons from ASD and control brains. If successful, the experiments proposed here will push the existing frontiers in human brain research, and for the first time, draw a connection between regulatory non-coding DNA, chromosomal architectures, and histone methylation profiles in multiple neuronal subtypes in health and disease.
This application will explore potential changes in chromatin (here defined as the organization and packaging of the genome inside the cell nucleus) in specific cell types collected from brain of subjects on the autism spectrum, in comparison to controls.
|Khan, Atlas; Liu, Qian; Wang, Kai (2018) iMEGES: integrated mental-disorder GEnome score by deep neural network for prioritizing the susceptibility genes for mental disorders in personal genomes. BMC Bioinformatics 19:501|
|Zhu, Ying; Sousa, André M M; Gao, Tianliuyun et al. (2018) Spatiotemporal transcriptomic divergence across human and macaque brain development. Science 362:|
|Amiri, Anahita; Coppola, Gianfilippo; Scuderi, Soraya et al. (2018) Transcriptome and epigenome landscape of human cortical development modeled in organoids. Science 362:|
|Rhie, Suhn K; Schreiner, Shannon; Witt, Heather et al. (2018) Using 3D epigenomic maps of primary olfactory neuronal cells from living individuals to understand gene regulation. Sci Adv 4:eaav8550|
|Toker, Lilah; Mancarci, Burak Ogan; Tripathy, Shreejoy et al. (2018) Transcriptomic Evidence for Alterations in Astrocytes and Parvalbumin Interneurons in Subjects With Bipolar Disorder and Schizophrenia. Biol Psychiatry 84:787-796|
|Wang, Daifeng; Liu, Shuang; Warrell, Jonathan et al. (2018) Comprehensive functional genomic resource and integrative model for the human brain. Science 362:|
|Li, Mingfeng; Santpere, Gabriel; Imamura Kawasawa, Yuka et al. (2018) Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science 362:|
|Bryois, Julien; Garrett, Melanie E; Song, Lingyun et al. (2018) Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia. Nat Commun 9:3121|
|Gusev, Alexander; Mancuso, Nicholas; Won, Hyejung et al. (2018) Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet 50:538-548|
|An, Joon-Yong; Lin, Kevin; Zhu, Lingxue et al. (2018) Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. Science 362:|
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