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EMBO Rep. 2017 Jul;18(7):1108-1122. doi: 10.15252/embr.201643534. Epub 2017 Jun 6.

Brd4-Brd2 isoform switching coordinates pluripotent exit and Smad2-dependent lineage specification.

Author information

1
The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, The University of Dundee, Dundee, UK.
2
Pluripotent Stem Cell Facility, School of Life Sciences, The University of Dundee, Dundee, UK.
3
Centre for Gene Regulation and Expression, School of Life Sciences, The University of Dundee, Dundee, UK.
4
Biological Chemistry and Drug Discovery, School of Life Sciences, The University of Dundee, Dundee, UK.
5
The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, The University of Dundee, Dundee, UK g.m.findlay@dundee.ac.uk.

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.

KEYWORDS:

BET Bromodomain; Nodal‐Smad2 signalling; Pluripotency; differentiation; embryonic stem cell

PMID:
28588073
PMCID:
PMC5494510
DOI:
10.15252/embr.201643534
[Indexed for MEDLINE]
Free PMC Article

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