Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions.

Autor:	Girskis KM; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA., Stergachis AB; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA., DeGennaro EM; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA., Doan RN; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Qian X; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Johnson MB; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA., Wang PP; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Sejourne GM; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Nagy MA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Pollina EA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Sousa AMM; Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA., Shin T; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston MA, USA., Kenny CJ; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Scotellaro JL; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Debo BM; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA., Gonzalez DM; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Rento LM; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Yeh RC; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Song JHT; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Beaudin M; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Fan J; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA., Kharchenko PV; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA., Sestan N; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Greenberg ME; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA., Walsh CA; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA. Electronic address: christopher.walsh@childrens.harvard.edu.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2021 Oct 20; Vol. 109 (20), pp. 3239-3251.e7. Date of Electronic Publication: 2021 Sep 02.
DOI:	10.1016/j.neuron.2021.08.005
Abstrakt:	Human accelerated regions (HARs) are the fastest-evolving regions of the human genome, and many are hypothesized to function as regulatory elements that drive human-specific gene regulatory programs. We interrogate the in vitro enhancer activity and in vivo epigenetic landscape of more than 3,100 HARs during human neurodevelopment, demonstrating that many HARs appear to act as neurodevelopmental enhancers and that sequence divergence at HARs has largely augmented their neuronal enhancer activity. Furthermore, we demonstrate PPP1R17 to be a putative HAR-regulated gene that has undergone remarkable rewiring of its cell type and developmental expression patterns between non-primates and primates and between non-human primates and humans. Finally, we show that PPP1R17 slows neural progenitor cell cycle progression, paralleling the cell cycle length increase seen predominantly in primate and especially human neurodevelopment. Our findings establish HARs as key components in rewiring human-specific neurodevelopmental gene regulatory programs and provide an integrated resource to study enhancer activity of specific HARs. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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