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An autoinhibitory switch of the LSD1 disordered region controls enhancer silencing

ABSTRACT: Transcriptional coregulators and transcription factors (TFs) contain intrinsically disordered regions (IDRs) that are critical for their partitioning and function in gene regulation. Canonically, IDRs drive coregulator-TF association by directly promoting multivalent protein-protein interactions. Using a chemical genetic approach, we report an unexpected mechanism by which 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 proteins structured domains with TF hubs. 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 that the dynamic crosstalk between opposing structured and unstructured regions is an alternative paradigm by which disordered regions can shape coregulator-transcription factor interactions to control cis-regulatory landscapes and cell fate.

INSTRUMENT(S): Q Exactive HF-X, Q Exactive HF, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Steven A. Carr

PROVIDER: MSV000094239 | MassIVE | Tue Mar 05 11:46:00 GMT 2024

REPOSITORIES: MassIVE

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