title: The genome in three dimensions: a new frontier in human brain research.
abstract: Less than 1.5% of the human genome encodes protein. However, vast portions of the human genome are subject to transcriptional and epigenetic regulation, and many noncoding regulatory DNA elements are thought to regulate the spatial organization of interphase chromosomes. For example, chromosomal "loopings" are pivotal for the orderly process of gene expression, by enabling distal regulatory enhancer or silencer elements to directly interact with proximal promoter and transcription start sites, potentially bypassing hundreds of kilobases of interspersed sequence on the linear genome. To date, however, epigenetic studies in the human brain are mostly limited to the exploration of DNA methylation and posttranslational modifications of the nucleosome core histones. In contrast, very little is known about the regulation of supranucleosomal structures. Here, we show that chromosome conformation capture, a widely used approach to study higher-order chromatin, is applicable to tissue collected postmortem, thereby informing about genome organization in the human brain. We introduce chromosome conformation capture protocols for brain and compare higher-order chromatin structures at the chromosome 6p22.2-22.1 schizophrenia and bipolar disorder susceptibility locus, and additional neurodevelopmental risk genes, (DPP10, MCPH1) in adult prefrontal cortex and various cell culture systems, including neurons derived from reprogrammed skin cells. We predict that the exploration of three-dimensional genome architectures and function will open up new frontiers in human brain research and psychiatric genetics and provide novel insights into the epigenetic risk architectures of regulatory noncoding DNA.
authors: Departments of Psychiatry and Neuroscience , Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Amanda C
authors: AC
authors: Mitchell
authors: Departments of Psychiatry and Neuroscience , Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Brudnick Neuropsychiatric Research Institute , University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Rahul
authors: R
authors: Bharadwaj
authors: Brudnick Neuropsychiatric Research Institute , University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Catheryne
authors: C
authors: Whittle
authors: Center for Regenerative Biology and Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut.
authors: Winfried
authors: W
authors: Krueger
authors: Department of Psychiatry, Vanderbilt University, Nashville, Tennessee.
authors: Karoly
authors: K
authors: Mirnics
authors: Departments of Psychiatry and Neuroscience , Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Yasmin
authors: Y
authors: Hurd
authors: Center for Regenerative Biology and Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut.
authors: Theodore
authors: T
authors: Rasmussen
authors: Departments of Psychiatry and Neuroscience , Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Brudnick Neuropsychiatric Research Institute , University of Massachusetts Medical School, Worcester, Massachusetts. Electronic address: schahram.akbarian@mssm.edu.
authors: Schahram
authors: S
authors: Akbarian
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D018929:Cell Culture Techniques; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D045584:Chromosome Positioning; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008959:Models, Neurological; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology
chemical_list: D002843:Chromatin
keywords: Chromatin fiber; chromosomal looping; chromosome conformation capture; genome in 3D; higher-order chromatin; human brain
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