The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells

Wai In Chan, Rebecca L. Hannah, Mark A. Dawson, Clare Pridans, Donna Foster, Anagha Joshi, Berthold Göttgens, Jan Van Deursen, Brian J P Huntly

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

The transcriptional coactivator Cbp plays an important role in a wide range of cellular processes, including proliferation, differentiation, and apoptosis. Although studies have shown its requirement for hematopoietic stem cell (HSC) development, its role in adult HSC maintenance, as well as the cellular and molecular mechanisms underlying Cbp function, is not clear. Here, we demonstrate a gradual loss of phenotypic HSCs and differentiation defects following conditional ablation of Cbp during adult homeostasis. In addition, Cbp-deficient HSCs reconstituted hematopoiesis with lower efficiency than their wild-type counterparts, and this response was readily exhausted under replicative stress. This phenotype relates to an alteration in cellular fate decisions for HSCs, with Cbp loss leading to an increase in differentiation, quiescence, and apoptosis. Genome-wide analyses of Cbp occupancy and differential gene expression upon Cbp deletion identified HSCspecific genes regulated by Cbp, providing a molecular basis for the phenotype. Finally, Cbp binding significantly overlapped at genes combinatorially bound by 7 major hematopoietic transcriptional regulators, linking Cbp to a critical HSC transcriptional regulatory network. Our data demonstrate that Cbp plays a role in adult HSC homeostasis by maintaining the balance between different HSC fate decisions, and our findings identify a putative HSC-specific transcriptional network coordinated by Cbp.

Original languageEnglish (US)
Pages (from-to)5046-5060
Number of pages15
JournalMolecular and Cellular Biology
Volume31
Issue number24
DOIs
StatePublished - Dec 2011

Fingerprint

Adult Stem Cells
Hematopoietic Stem Cells
Gene Regulatory Networks
Homeostasis
Apoptosis
Phenotype
Hematopoiesis
Genes
Maintenance
Genome
Gene Expression

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Chan, W. I., Hannah, R. L., Dawson, M. A., Pridans, C., Foster, D., Joshi, A., ... Huntly, B. J. P. (2011). The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells. Molecular and Cellular Biology, 31(24), 5046-5060. https://doi.org/doi:10.1128/MCB.05830-11

The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells. / Chan, Wai In; Hannah, Rebecca L.; Dawson, Mark A.; Pridans, Clare; Foster, Donna; Joshi, Anagha; Göttgens, Berthold; Van Deursen, Jan; Huntly, Brian J P.

In: Molecular and Cellular Biology, Vol. 31, No. 24, 12.2011, p. 5046-5060.

Research output: Contribution to journalArticle

Chan, WI, Hannah, RL, Dawson, MA, Pridans, C, Foster, D, Joshi, A, Göttgens, B, Van Deursen, J & Huntly, BJP 2011, 'The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells', Molecular and Cellular Biology, vol. 31, no. 24, pp. 5046-5060. https://doi.org/doi:10.1128/MCB.05830-11
Chan, Wai In ; Hannah, Rebecca L. ; Dawson, Mark A. ; Pridans, Clare ; Foster, Donna ; Joshi, Anagha ; Göttgens, Berthold ; Van Deursen, Jan ; Huntly, Brian J P. / The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells. In: Molecular and Cellular Biology. 2011 ; Vol. 31, No. 24. pp. 5046-5060.
@article{08b2014dbd6146589de26ad6ce9fc045,
title = "The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells",
abstract = "The transcriptional coactivator Cbp plays an important role in a wide range of cellular processes, including proliferation, differentiation, and apoptosis. Although studies have shown its requirement for hematopoietic stem cell (HSC) development, its role in adult HSC maintenance, as well as the cellular and molecular mechanisms underlying Cbp function, is not clear. Here, we demonstrate a gradual loss of phenotypic HSCs and differentiation defects following conditional ablation of Cbp during adult homeostasis. In addition, Cbp-deficient HSCs reconstituted hematopoiesis with lower efficiency than their wild-type counterparts, and this response was readily exhausted under replicative stress. This phenotype relates to an alteration in cellular fate decisions for HSCs, with Cbp loss leading to an increase in differentiation, quiescence, and apoptosis. Genome-wide analyses of Cbp occupancy and differential gene expression upon Cbp deletion identified HSCspecific genes regulated by Cbp, providing a molecular basis for the phenotype. Finally, Cbp binding significantly overlapped at genes combinatorially bound by 7 major hematopoietic transcriptional regulators, linking Cbp to a critical HSC transcriptional regulatory network. Our data demonstrate that Cbp plays a role in adult HSC homeostasis by maintaining the balance between different HSC fate decisions, and our findings identify a putative HSC-specific transcriptional network coordinated by Cbp.",
author = "Chan, {Wai In} and Hannah, {Rebecca L.} and Dawson, {Mark A.} and Clare Pridans and Donna Foster and Anagha Joshi and Berthold G{\"o}ttgens and {Van Deursen}, Jan and Huntly, {Brian J P}",
year = "2011",
month = "12",
doi = "doi:10.1128/MCB.05830-11",
language = "English (US)",
volume = "31",
pages = "5046--5060",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "24",

}

TY - JOUR

T1 - The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells

AU - Chan, Wai In

AU - Hannah, Rebecca L.

AU - Dawson, Mark A.

AU - Pridans, Clare

AU - Foster, Donna

AU - Joshi, Anagha

AU - Göttgens, Berthold

AU - Van Deursen, Jan

AU - Huntly, Brian J P

PY - 2011/12

Y1 - 2011/12

N2 - The transcriptional coactivator Cbp plays an important role in a wide range of cellular processes, including proliferation, differentiation, and apoptosis. Although studies have shown its requirement for hematopoietic stem cell (HSC) development, its role in adult HSC maintenance, as well as the cellular and molecular mechanisms underlying Cbp function, is not clear. Here, we demonstrate a gradual loss of phenotypic HSCs and differentiation defects following conditional ablation of Cbp during adult homeostasis. In addition, Cbp-deficient HSCs reconstituted hematopoiesis with lower efficiency than their wild-type counterparts, and this response was readily exhausted under replicative stress. This phenotype relates to an alteration in cellular fate decisions for HSCs, with Cbp loss leading to an increase in differentiation, quiescence, and apoptosis. Genome-wide analyses of Cbp occupancy and differential gene expression upon Cbp deletion identified HSCspecific genes regulated by Cbp, providing a molecular basis for the phenotype. Finally, Cbp binding significantly overlapped at genes combinatorially bound by 7 major hematopoietic transcriptional regulators, linking Cbp to a critical HSC transcriptional regulatory network. Our data demonstrate that Cbp plays a role in adult HSC homeostasis by maintaining the balance between different HSC fate decisions, and our findings identify a putative HSC-specific transcriptional network coordinated by Cbp.

AB - The transcriptional coactivator Cbp plays an important role in a wide range of cellular processes, including proliferation, differentiation, and apoptosis. Although studies have shown its requirement for hematopoietic stem cell (HSC) development, its role in adult HSC maintenance, as well as the cellular and molecular mechanisms underlying Cbp function, is not clear. Here, we demonstrate a gradual loss of phenotypic HSCs and differentiation defects following conditional ablation of Cbp during adult homeostasis. In addition, Cbp-deficient HSCs reconstituted hematopoiesis with lower efficiency than their wild-type counterparts, and this response was readily exhausted under replicative stress. This phenotype relates to an alteration in cellular fate decisions for HSCs, with Cbp loss leading to an increase in differentiation, quiescence, and apoptosis. Genome-wide analyses of Cbp occupancy and differential gene expression upon Cbp deletion identified HSCspecific genes regulated by Cbp, providing a molecular basis for the phenotype. Finally, Cbp binding significantly overlapped at genes combinatorially bound by 7 major hematopoietic transcriptional regulators, linking Cbp to a critical HSC transcriptional regulatory network. Our data demonstrate that Cbp plays a role in adult HSC homeostasis by maintaining the balance between different HSC fate decisions, and our findings identify a putative HSC-specific transcriptional network coordinated by Cbp.

UR - http://www.scopus.com/inward/record.url?scp=83255164950&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83255164950&partnerID=8YFLogxK

U2 - doi:10.1128/MCB.05830-11

DO - doi:10.1128/MCB.05830-11

M3 - Article

C2 - 22006020

AN - SCOPUS:83255164950

VL - 31

SP - 5046

EP - 5060

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 24

ER -