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Science. 2018 Dec 14;362(6420). pii: eaat4311. doi: 10.1126/science.aat4311.

Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk.

Author information

1
Icahn School of Medicine M.D./Ph.D. Program, Icahn School of Medicine at Mount Sinai, New York, NY 10027, USA.
2
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10027, USA.
3
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10027, USA.
4
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10027, USA.
5
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
6
New York Genome Center, New York, NY 10013, USA.
7
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10027, USA.
8
Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
9
Neuropsychiatric Signaling Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
10
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10027, USA. schahram.akbarian@mssm.edu.

Abstract

To explore the developmental reorganization of the three-dimensional genome of the brain in the context of neuropsychiatric disease, we monitored chromosomal conformations in differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread developmental remodeling of the chromosomal contact map and included interactions anchored in common variant sequences that confer heritable risk for schizophrenia. We describe cell type-specific chromosomal connectomes composed of schizophrenia risk variants and their distal targets, which altogether show enrichment for genes that regulate neuronal connectivity and chromatin remodeling, and evidence for coordinated transcriptional regulation and proteomic interaction of the participating genes. Developmentally regulated chromosomal conformation changes at schizophrenia-relevant sequences disproportionally occurred in neurons, highlighting the existence of cell type-specific disease risk vulnerabilities in spatial genome organization.

PMID:
30545851
DOI:
10.1126/science.aat4311
[Indexed for MEDLINE]

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