AUTS2 confers gene activation to Polycomb group proteins in the CNS

Details

• Alternative Title:
  Nature
• Personal Author:
  Gao, Zhonghua ; Lee, Pedro ; Stafford, James M. ; von Schimmelmann, Melanie ; Schaefer, Anne ; Reinberg, Danny
• Description:
  Naturally occurring variations of Polycomb repressive complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, autism susceptibility candidate 2 (AUTS2). Although AUTS2 is often disrupted in patients with neuronal disorders, the mechanism underlying the pathogenesis is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of P300 leads to gene activation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrated that AUTS2 regulates neuronal gene expression through promoter association. Conditional targeting of Auts2 in the mouse central nervous system (CNS) leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.
• Subjects:
  Animals Article Behavior, Animal Cell Cycle Proteins Central Nervous System Female Gene Expression Profiling Gene Expression Regulation Gene Knockout Techniques Genotype HEK293 Cells Histones Humans Male Mice Mice, Inbred C57BL Phosphorylation Proteins Ubiquitination

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• Source:
  Nature. 516(7531):349-354.
• Pubmed ID:
  25519132
• Pubmed Central ID:
  PMC4323097
• Document Type:
  Journal Article
• Funding:
  P30 CA016087/CA/NCI NIH HHS/United States ; 5T32CA160002/CA/NCI NIH HHS/United States ; DP2 MH100012/MH/NIMH NIH HHS/United States ; GM-64844/GM/NIGMS NIH HHS/United States ; 1F32GM105275/GM/NIGMS NIH HHS/United States ; R01 GM064844/GM/NIGMS NIH HHS/United States ; Howard Hughes Medical Institute/United States ; F32AA022842/AA/NIAAA NIH HHS/United States ; 1DP2MH100012-01/DP/NCCDPHP CDC HHS/United States ; T32 CA160002/CA/NCI NIH HHS/United States ; F32 AA022842/AA/NIAAA NIH HHS/United States ; F32 GM105275/GM/NIGMS NIH HHS/United States
• Volume:
  516
• Issue:
  7531
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:0970491812819ced9052f3000e016d6834b2c2bdff1abb6a18309ea8b51bf5a1
• Download URL:
  https://stacks.cdc.gov/view/cdc/30283/cdc_30283_DS1.pdf
• File Type:
  [PDF - 4.27 MB ]