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

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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

Fingerprint

Regulator Genes
Protein Isoforms
Genes
Specifications
Pluripotent Stem Cells
Stem cells
Smad2 Protein
Gene expression
Liver
Neurons
Muscle
Pancreas
Myocardium
Proteins
Down-Regulation
Chemical activation
Maintenance
Tissue
Gene Expression
Molecules

Keywords

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

Cite this

@article{86244101dc3341f3a29b2465d879f6df,
title = "BRD4-BRD2 isoform switching coordinates pluripotent exit and Smad2-dependent lineage specification",
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, Differentiation, Embryonic stem cell, Nodal-Smad2 signalling, Pluripotency",
author = "Rosalia Fernandez-Alonso and Lindsay Davidson and Jens Hukelmann and Michael Zengerle and Prescott, {Alan R.} and Angus Lamond and Alessio Ciulli and Sapkota, {Gopal P.} and Findlay, {Greg M.}",
note = "The authors would like to thank Prof. Helen Walden (MRC-PPU, Dundee) and Dr. Tobias Beyer (ETH, Zurich) for critical reading of the manuscript, and Profs. Kate Storey, Doreen Cantrell and Vicky Cowling and Dr. Kim Dale (School of Life Sciences, University of Dundee) for advice and critical insights. This work was funded by Tenovus Scotland research grant (T11/15). G.M.F. is supported in part by a Medical Research Council New Investigator Award MR/N000609/1, and A.C. is funded in part by a European Research Council Starting Grant ERC-2012-StG-311460.",
year = "2017",
month = "6",
doi = "10.15252/embr.201643534",
language = "English",
volume = "18",
pages = "859--1037",
journal = "EMBO Reports",
issn = "1469-221X",
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}

TY - JOUR

T1 - BRD4-BRD2 isoform switching coordinates pluripotent exit and Smad2-dependent lineage specification

AU - Fernandez-Alonso, Rosalia

AU - Davidson, Lindsay

AU - Hukelmann, Jens

AU - Zengerle, Michael

AU - Prescott, Alan R.

AU - Lamond, Angus

AU - Ciulli, Alessio

AU - Sapkota, Gopal P.

AU - Findlay, Greg M.

N1 - The authors would like to thank Prof. Helen Walden (MRC-PPU, Dundee) and Dr. Tobias Beyer (ETH, Zurich) for critical reading of the manuscript, and Profs. Kate Storey, Doreen Cantrell and Vicky Cowling and Dr. Kim Dale (School of Life Sciences, University of Dundee) for advice and critical insights. This work was funded by Tenovus Scotland research grant (T11/15). G.M.F. is supported in part by a Medical Research Council New Investigator Award MR/N000609/1, and A.C. is funded in part by a European Research Council Starting Grant ERC-2012-StG-311460.

PY - 2017/6

Y1 - 2017/6

N2 - 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.

AB - 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.

KW - BET Bromodomain

KW - Differentiation

KW - Embryonic stem cell

KW - Nodal-Smad2 signalling

KW - Pluripotency

U2 - 10.15252/embr.201643534

DO - 10.15252/embr.201643534

M3 - Article

VL - 18

SP - 859

EP - 1037

JO - EMBO Reports

JF - EMBO Reports

SN - 1469-221X

IS - 6

M1 - e201643534

ER -