Publication Date:
2014-12-19
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323097/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323097/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Zhonghua -- Lee, Pedro -- Stafford, James M -- von Schimmelmann, Melanie -- Schaefer, Anne -- Reinberg, Danny -- 1DP2MH100012-01/DP/NCCDPHP CDC HHS/ -- 1F32GM105275/GM/NIGMS NIH HHS/ -- 5T32CA160002/CA/NCI NIH HHS/ -- DP2 MH100012/MH/NIMH NIH HHS/ -- F32AA022842/AA/NIAAA NIH HHS/ -- GM-64844/GM/NIGMS NIH HHS/ -- P30 CA016087/CA/NCI NIH HHS/ -- R01 GM064844/GM/NIGMS NIH HHS/ -- T32 CA160002/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 18;516(7531):349-54. doi: 10.1038/nature13921.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, New York University Langone School of Medicine, Department of Biochemistry and Molecular Pharmacology, New York, New York 10016, USA. ; Friedman Brain Institute, Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25519132" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Behavior, Animal/physiology
;
Cell Cycle Proteins/genetics/*metabolism
;
Central Nervous System/*metabolism
;
Female
;
Gene Expression Profiling
;
Gene Expression Regulation/*genetics
;
Gene Knockout Techniques
;
Genotype
;
HEK293 Cells
;
Histones/metabolism
;
Humans
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Phosphorylation
;
Proteins/genetics/*metabolism
;
Ubiquitination
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
