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An autoinhibitory switch of the LSD1 disordered region controls enhancer silencing.
Waterbury, Amanda L; Kwok, Hui Si; Lee, Ceejay; Narducci, Domenic N; Freedy, Allyson M; Su, Cindy; Raval, Shaunak; Reiter, Andrew H; Hawkins, William; Lee, Kwangwoon; Li, Jiaming; Hoenig, Samuel M; Vinyard, Michael E; Cole, Philip A; Hansen, Anders S; Carr, Steven A; Papanastasiou, Malvina; Liau, Brian B.
Afiliação
  • Waterbury AL; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Kwok HS; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Lee C; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Narducci DN; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA.
  • Freedy AM; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Su C; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Raval S; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Reiter AH; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Hawkins W; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Lee K; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • Li J; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Hoenig SM; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Vinyard ME; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Cole PA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • Hansen AS; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA.
  • Carr SA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Papanastasiou M; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Liau BB; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: liau@chemistry.harvard.edu.
Mol Cell ; 84(12): 2238-2254.e11, 2024 Jun 20.
Article em En | MEDLINE | ID: mdl-38870936
ABSTRACT
Transcriptional coregulators and transcription factors (TFs) contain intrinsically disordered regions (IDRs) that are critical for their association and function in gene regulation. More recently, IDRs have been shown to promote multivalent protein-protein interactions between coregulators and TFs to drive their association into condensates. By contrast, here we demonstrate how the IDR of the corepressor LSD1 excludes TF association, acting as a dynamic conformational switch that tunes repression of active cis-regulatory elements. Hydrogen-deuterium exchange shows that the LSD1 IDR interconverts between transient open and closed conformational states, the latter of which inhibits partitioning of the protein's structured domains with TF condensates. This autoinhibitory switch controls leukemic differentiation by modulating repression of active cis-regulatory elements bound by LSD1 and master hematopoietic TFs. Together, these studies unveil alternative mechanisms by which disordered regions and their dynamic crosstalk with structured regions can shape coregulator-TF interactions to control cis-regulatory landscapes and cell fate.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Elementos Facilitadores Genéticos / Histona Desmetilases Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Elementos Facilitadores Genéticos / Histona Desmetilases Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article