1. NRF1 Association with AUTS2-Polycomb Mediates Specific Gene Activation in the Brain
- Author
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Andrew Swale, Nicolas Descostes, William B. Dobyns, Sanxiong Liu, Christiane Zweier, Chai-An Mao, Ivan Ivanovski, Danny Reinberg, Livia Garavelli, Megan T. Cho, James M. Stafford, Wukui Zhao, Tudor C. Badea, Pedro Lee, Kimberly A. Aldinger, Orsetta Zuffardi, Takae Kiyama, Jennifer B. Humberson, M. Scott Perry, Astrid Weber, Edoardo Errichiello, Stefano Giuseppe Caraffi, Hanna K. McNamara, Michael C. Schneider, Antigone Papavasiliou, Chi Vicky Cheng, Mitali Dave, University of Zurich, and Reinberg, Danny
- Subjects
Male ,Proteomics ,Transcriptional Activation ,Heterozygote ,10039 Institute of Medical Genetics ,Heterochromatin ,610 Medicine & health ,Context (language use) ,macromolecular substances ,Biology ,medicine.disease_cause ,Article ,1307 Cell Biology ,Mice ,Protein Domains ,Transcription (biology) ,1312 Molecular Biology ,medicine ,Animals ,Humans ,NRF1 ,EP300 ,Molecular Biology ,Transcription factor ,Embryonic Stem Cells ,Neurons ,Regulation of gene expression ,Mutation ,Nuclear Respiratory Factor 1 ,Brain ,Cell Differentiation ,Cell Biology ,Genomics ,CREB-Binding Protein ,Chromatin ,Cell biology ,Cytoskeletal Proteins ,HEK293 Cells ,570 Life sciences ,biology ,Female ,E1A-Associated p300 Protein ,Protein Binding ,Transcription Factors - Abstract
SUMMARYThe heterogeneous complexes comprising the family of Polycomb Repressive Complex 1 (PRC1) are instrumental to establishing facultative heterochromatin that is repressive to transcription. Yet, two PRC1 species, PRC1.3 and PRC1.5, are known to comprise novel components, AUTS2, P300, and CK2 that convert this repressive function to that of transcription activation. Here, we report that patients harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mostly associated with a heterozygous pathogenic variant inCREBBP/EP300. As well, the absence of AUTS2 gives rise to a mis-regulation of a subset of developmental genes and curtails motor neuron differentiation from embryonic stem cells in the context of a well-defined system. Moreover, the transcription factor, Nuclear Respiratory Factor 1 (NRF1) exhibits a novel and integral role in this aspect of the neurodevelopmental process, being required for PRC1.3 recruitment to chromatin.
- Published
- 2021
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