BRD4-BRD2 isoform switching coordinates pluripotent exit and Smad2-dependent lineage specification

Rosalia Fernandez-Alonso, Lindsay Davidson, Jens Hukelmann, Michael Zengerle, Alan R. Prescott, Angus Lamond, Alessio Ciulli, Gopal P. Sapkota, Greg M. Findlay (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)
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Abstract

Pluripotent Stem Cells (PSCs) hold great clinical potential, as they possess the capacity to differentiate into fully specialised tissues such as pancreas, liver, neurons and cardiac muscle. However, the molecular mechanisms that coordinate pluripotent exit with lineage specification remain poorly understood. To address this question, we perform a small molecule screen to systematically identify novel regulators of the Smad2 signalling network, a key determinant of PSC fate. We reveal an essential function for BET family bromodomain proteins in Smad2 activation, distinct from the role of Brd4 in pluripotency maintenance. Mechanistically, BET proteins specifically engage Nodal gene regulatory elements (NREs) to promote Nodal signalling and Smad2 developmental responses. In pluripotent cells, Brd2-Brd4 occupy NREs, but only Brd4 is required for pluripotency gene expression. Brd4 downregulation facilitates pluripotent exit and drives enhanced Brd2 NRE occupancy, thereby unveiling a specific function for Brd2 in differentiative Nodal-Smad2 signalling. Therefore, distinct BET functionalities and Brd4-Brd2 isoform switching at NREs coordinate pluripotent exit with lineage specification.
Original languageEnglish
Article numbere201643534
Pages (from-to)859-1037
Number of pages178
JournalEMBO Reports
Volume18
Issue number6
Early online date6 Jun 2017
DOIs
Publication statusPublished - Jun 2017

Keywords

  • BET Bromodomain
  • Differentiation
  • Embryonic stem cell
  • Nodal-Smad2 signalling
  • Pluripotency

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