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Curr Opin Neurobiol. 2019 Jun 27;59:112-119. doi: 10.1016/j.conb.2019.05.007. [Epub ahead of print]

Spatial genome exploration in the context of cognitive and neurological disease.

Author information

1
Icahn School of Medicine MD/PhD Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
3
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; New York Genome Center, New York, NY 10013, USA.
4
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China.
6
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: schahram.akbarian@mssm.edu.

Abstract

The 'non-linear' genome, or the spatial proximity of non-contiguous sequences, emerges as an important regulatory layer for genome organization and function, including transcriptional regulation. Here, we review recent genome-scale chromosome conformation mappings ('Hi-C') in developing and adult human and mouse brain. Neural differentiation is associated with widespread remodeling of the chromosomal contact map, reflecting dynamic changes in cell-type-specific gene expression programs, with a massive (estimated 20-50%) net loss of chromosomal contacts that is specific for the neuronal lineage. Hi-C datasets provided an unexpected link between locus-specific abnormal expansion of repeat sequences positioned at the boundaries of self-associating topological chromatin domains, and monogenic neurodevelopmental and neurodegenerative disease. Furthermore, integrative cell-type-specific Hi-C and transcriptomic analysis uncovered an expanded genomic risk space for sequences conferring liability for schizophrenia and other cognitive disease. We predict that spatial genome exploration will deliver radically new insights into the brain nucleome in health and disease.

PMID:
31255842
DOI:
10.1016/j.conb.2019.05.007

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