Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions,Neuron

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Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions
Neuron ( IF 16.2 ) Pub Date : 2021-09-02 , DOI: 10.1016/j.neuron.2021.08.005
Kelly M Girskis ₁ , Andrew B Stergachis ₂ , Ellen M DeGennaro ₃ , Ryan N Doan ₄ , Xuyu Qian ₄ , Matthew B Johnson ₅ , Peter P Wang ₄ , Gabrielle M Sejourne ₄ , M Aurel Nagy ₆ , Elizabeth A Pollina ₇ , André M M Sousa ₈ , Taehwan Shin ₉ , Connor J Kenny ₄ , Julia L Scotellaro ₁₀ , Brian M Debo ₁₁ , Dilenny M Gonzalez ₄ , Lariza M Rento ₄ , Rebecca C Yeh ₄ , Janet H T Song ₄ , Marc Beaudin ₄ , Jean Fan ₁₂ , Peter V Kharchenko ₁₃ , Nenad Sestan ₁₄ , Michael E Greenberg ₁₅ , Christopher A Walsh ₁

Affiliation

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.
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
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.
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 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.
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.
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.
Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA.
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.
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.
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA.
Department of Neurobiology, 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; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.

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.

中文翻译：

人类加速区域对人类神经发育基因调控程序的重新布线

人类加速区域 (HAR) 是人类基因组中发展最快的区域，许多区域被假设为驱动人类特定基因调控程序的调控元件。我们在人类神经发育过程中询问了3,100 多个 HARs的体外增强子活性和体内表观遗传景观，证明许多 HARs 似乎充当神经发育增强剂，并且 HARs 的序列差异在很大程度上增强了它们的神经元增强子活性。此外，我们证明PPP1R17是一种推定的 HAR 调节基因，其细胞类型和非灵长类动物与灵长类动物之间以及非人类灵长类动物与人类之间的发育表达模式发生了显着的重新连接。最后，我们证明PPP1R17减缓神经祖细胞周期进程，与主要在灵长类动物尤其是人类神经发育中看到的细胞周期长度增加平行。我们的研究结果将 HAR 确立为重新连接人类特异性神经发育基因调控程序的关键组成部分，并为研究特定 HAR 的增强子活性提供了综合资源。

更新日期：2021-10-20

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