Cited2 is an Essential Regulator of Adult Hematopoietic Stem Cells

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2009 Dec 3

PMID 19951693

Citations 61

Authors

Kamil R Kranc

Hein Schepers

Neil P Rodrigues

Simon Bamforth

Ellen Villadsen

Helen Ferry

Tiphaine Bouriez-Jones

Mikael Sigvardsson

Shoumo Bhattacharya

Sten Eirik Jacobsen

Tariq Enver

Affiliations

Soon will be listed here.

Abstract

The regulatory pathways necessary for the maintenance of adult hematopoietic stem cells (HSCs) remain poorly defined. By using loss-of-function approaches, we report a selective and cell-autonomous requirement for the p300/CBP-binding transcriptional coactivator Cited2 in adult HSC maintenance. Conditional deletion of Cited2 in the adult mouse results in loss of HSCs causing multilineage bone marrow failure and increased lethality. In contrast, conditional ablation of Cited2 after lineage specification in lymphoid and myeloid lineages has no impact on the maintenance of these lineages. Additional deletion of Ink4a/Arf (encoding p16(Ink4a) and p19(Arf)) or Trp53 (encoding p53, a downstream target of p19(Arf)) in a Cited2-deficient background restores HSC functionality and rescues mice from bone marrow failure. Furthermore, we show that the critical role of Cited2 in primitive hematopoietic cells is conserved in humans. Taken together, our studies provide genetic evidence that Cited2 selectively maintains adult HSC functions, at least in part, via Ink4a/Arf and Trp53.

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References

Tien E, Davis J, Vanden Heuvel J . Identification of the CREB-binding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor alpha coregulator. J Biol Chem. 2004; 279(23):24053-63. DOI: 10.1074/jbc.M401489200. View

POMERANTZ J, Schreiber-Agus N, Liegeois N, Silverman A, Alland L, Chin L . The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell. 1998; 92(6):713-23. DOI: 10.1016/s0092-8674(00)81400-2. View

Pritsker M, Ford N, Jenq H, Lemischka I . Genomewide gain-of-function genetic screen identifies functionally active genes in mouse embryonic stem cells. Proc Natl Acad Sci U S A. 2006; 103(18):6946-51. PMC: 1458999. DOI: 10.1073/pnas.0509861103. View

Chen Y, Haviernik P, Bunting K, Yang Y . Cited2 is required for normal hematopoiesis in the murine fetal liver. Blood. 2007; 110(8):2889-98. PMC: 2018670. DOI: 10.1182/blood-2007-01-066316. View

Qian Z, Chen L, Fernald A, Williams B, Le Beau M . A critical role for Apc in hematopoietic stem and progenitor cell survival. J Exp Med. 2008; 205(9):2163-75. PMC: 2526209. DOI: 10.1084/jem.20080578. View

Rebel V, Kung A, Tanner E, Yang H, Bronson R, Livingston D . Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal. Proc Natl Acad Sci U S A. 2002; 99(23):14789-94. PMC: 137497. DOI: 10.1073/pnas.232568499. View

Sun H, Zhu Y, Yin T, Sledge G, Yang Y . MRG1, the product of a melanocyte-specific gene related gene, is a cytokine-inducible transcription factor with transformation activity. Proc Natl Acad Sci U S A. 1998; 95(23):13555-60. PMC: 24857. DOI: 10.1073/pnas.95.23.13555. View

Opferman J, Letai A, Beard C, Sorcinelli M, Ong C, Korsmeyer S . Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature. 2003; 426(6967):671-6. DOI: 10.1038/nature02067. View

MacDonald S, Bamforth S, Chen C, Farthing C, Franklyn A, Broadbent C . Epiblastic Cited2 deficiency results in cardiac phenotypic heterogeneity and provides a mechanism for haploinsufficiency. Cardiovasc Res. 2008; 79(3):448-57. PMC: 2492730. DOI: 10.1093/cvr/cvn101. View

10.

Gomes I, Sharma T, Edassery S, Fulton N, Mar B, Westbrook C . Novel transcription factors in human CD34 antigen-positive hematopoietic cells. Blood. 2002; 100(1):107-19. DOI: 10.1182/blood.v100.1.107. View

11.

Qu X, Lam E, Doughman Y, Chen Y, Chou Y, Lam M . Cited2, a coactivator of HNF4alpha, is essential for liver development. EMBO J. 2007; 26(21):4445-56. PMC: 2063472. DOI: 10.1038/sj.emboj.7601883. View

12.

Opferman J, Iwasaki H, Ong C, Suh H, Mizuno S, Akashi K . Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science. 2005; 307(5712):1101-4. DOI: 10.1126/science.1106114. View

13.

Glenn D, Maurer R . MRG1 binds to the LIM domain of Lhx2 and may function as a coactivator to stimulate glycoprotein hormone alpha-subunit gene expression. J Biol Chem. 1999; 274(51):36159-67. DOI: 10.1074/jbc.274.51.36159. View

14.

Kranc K, Bamforth S, Braganca J, Norbury C, van Lohuizen M, Bhattacharya S . Transcriptional coactivator Cited2 induces Bmi1 and Mel18 and controls fibroblast proliferation via Ink4a/ARF. Mol Cell Biol. 2003; 23(21):7658-66. PMC: 207593. DOI: 10.1128/MCB.23.21.7658-7666.2003. View

15.

Yin Z, Haynie J, Yang X, Han B, Kiatchoosakun S, Restivo J . The essential role of Cited2, a negative regulator for HIF-1alpha, in heart development and neurulation. Proc Natl Acad Sci U S A. 2002; 99(16):10488-93. PMC: 124951. DOI: 10.1073/pnas.162371799. View

16.

Oguro H, Iwama A, Morita Y, Kamijo T, van Lohuizen M, Nakauchi H . Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice. J Exp Med. 2006; 203(10):2247-53. PMC: 2118102. DOI: 10.1084/jem.20052477. View

17.

Hock H, Meade E, Medeiros S, Schindler J, Valk P, Fujiwara Y . Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes Dev. 2004; 18(19):2336-41. PMC: 522982. DOI: 10.1101/gad.1239604. View

18.

Liu Y, Elf S, Miyata Y, Sashida G, Liu Y, Huang G . p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell. 2009; 4(1):37-48. PMC: 2839936. DOI: 10.1016/j.stem.2008.11.006. View

19.

Zhong J, Zhao Y, Sutton S, Su A, Zhan Y, Zhu L . Gene expression profile of murine long-term reconstituting vs. short-term reconstituting hematopoietic stem cells. Proc Natl Acad Sci U S A. 2005; 102(7):2448-53. PMC: 548308. DOI: 10.1073/pnas.0409459102. View

20.

Orkin S, Zon L . Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008; 132(4):631-44. PMC: 2628169. DOI: 10.1016/j.cell.2008.01.025. View