Nuclear Adaptor Ldb1 Regulates a Transcriptional Program Essential for the Maintenance of Hematopoietic Stem Cells

Overview

Journal Nat Immunol

Date 2010 Dec 28

PMID 21186366

Citations 73

Authors

Liqi Li

Raja Jothi

Kairong Cui

Jan Y Lee

Tsadok Cohen

Marat Gorivodsky

Itai Tzchori

Yangu Zhao

Sandra M Hayes

Emery H Bresnick

Keji Zhao

Heiner Westphal

Paul E Love

Affiliations

Soon will be listed here.

Abstract

The nuclear adaptor Ldb1 functions as a core component of multiprotein transcription complexes that regulate differentiation in diverse cell types. In the hematopoietic lineage, Ldb1 forms a complex with the non-DNA-binding adaptor Lmo2 and the transcription factors E2A, Scl and GATA-1 (or GATA-2). Here we demonstrate a critical and continuous requirement for Ldb1 in the maintenance of both fetal and adult mouse hematopoietic stem cells (HSCs). Deletion of Ldb1 in hematopoietic progenitors resulted in the downregulation of many transcripts required for HSC maintenance. Genome-wide profiling by chromatin immunoprecipitation followed by sequencing (ChIP-Seq) identified Ldb1 complex-binding sites at highly conserved regions in the promoters of genes involved in HSC maintenance. Our results identify a central role for Ldb1 in regulating the transcriptional program responsible for the maintenance of HSCs.

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References

Warren A, Colledge W, Carlton M, Evans M, Smith A, Rabbitts T . The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development. Cell. 1994; 78(1):45-57. DOI: 10.1016/0092-8674(94)90571-1. View

Landry J, Kinston S, Knezevic K, de Bruijn M, Wilson N, Nottingham W . Runx genes are direct targets of Scl/Tal1 in the yolk sac and fetal liver. Blood. 2008; 111(6):3005-14. DOI: 10.1182/blood-2007-07-098830. View

Grass J, Jing H, Kim S, Martowicz M, Pal S, Blobel G . Distinct functions of dispersed GATA factor complexes at an endogenous gene locus. Mol Cell Biol. 2006; 26(19):7056-67. PMC: 1592882. DOI: 10.1128/MCB.01033-06. View

Meier N, Krpic S, Rodriguez P, Strouboulis J, Monti M, Krijgsveld J . Novel binding partners of Ldb1 are required for haematopoietic development. Development. 2006; 133(24):4913-23. DOI: 10.1242/dev.02656. View

Boyer L, Lee T, Cole M, Johnstone S, Levine S, Zucker J . Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005; 122(6):947-56. PMC: 3006442. DOI: 10.1016/j.cell.2005.08.020. View

Jothi R, Cuddapah S, Barski A, Cui K, Zhao K . Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Res. 2008; 36(16):5221-31. PMC: 2532738. DOI: 10.1093/nar/gkn488. View

Kisanuki Y, Hammer R, Miyazaki J, Williams S, Richardson J, Yanagisawa M . Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Dev Biol. 2001; 230(2):230-42. DOI: 10.1006/dbio.2000.0106. View

Wadman I, Osada H, Grutz G, Agulnick A, Westphal H, Forster A . The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. EMBO J. 1997; 16(11):3145-57. PMC: 1169933. DOI: 10.1093/emboj/16.11.3145. View

Rodrigues N, Janzen V, Forkert R, Dombkowski D, Boyd A, Orkin S . Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis. Blood. 2005; 106(2):477-84. DOI: 10.1182/blood-2004-08-2989. View

10.

Barski A, Cuddapah S, Cui K, Roh T, Schones D, Wang Z . High-resolution profiling of histone methylations in the human genome. Cell. 2007; 129(4):823-37. DOI: 10.1016/j.cell.2007.05.009. View

11.

Anguita E, Hughes J, Heyworth C, Blobel G, Wood W, Higgs D . Globin gene activation during haemopoiesis is driven by protein complexes nucleated by GATA-1 and GATA-2. EMBO J. 2004; 23(14):2841-52. PMC: 514941. DOI: 10.1038/sj.emboj.7600274. View

12.

Souroullas G, Salmon J, Sablitzky F, Curtis D, Goodell M . Adult hematopoietic stem and progenitor cells require either Lyl1 or Scl for survival. Cell Stem Cell. 2009; 4(2):180-6. PMC: 2672304. DOI: 10.1016/j.stem.2009.01.001. View

13.

Semerad C, Mercer E, Inlay M, Weissman I, Murre C . E2A proteins maintain the hematopoietic stem cell pool and promote the maturation of myelolymphoid and myeloerythroid progenitors. Proc Natl Acad Sci U S A. 2009; 106(6):1930-5. PMC: 2644141. DOI: 10.1073/pnas.0808866106. View

14.

Xu Z, Huang S, Chang L, Agulnick A, Brandt S . Identification of a TAL1 target gene reveals a positive role for the LIM domain-binding protein Ldb1 in erythroid gene expression and differentiation. Mol Cell Biol. 2003; 23(21):7585-99. PMC: 207591. DOI: 10.1128/MCB.23.21.7585-7599.2003. View

15.

Majewski I, Blewitt M, de Graaf C, McManus E, Bahlo M, Hilton A . Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell activity. PLoS Biol. 2008; 6(4):e93. PMC: 2292752. DOI: 10.1371/journal.pbio.0060093. View

16.

Grutz G, Bucher K, Lavenir I, Larson T, Larson R, Rabbitts T . The oncogenic T cell LIM-protein Lmo2 forms part of a DNA-binding complex specifically in immature T cells. EMBO J. 1998; 17(16):4594-605. PMC: 1170789. DOI: 10.1093/emboj/17.16.4594. View

17.

Adolfsson J, Borge O, Bryder D, Theilgaard-Monch K, Sitnicka E, Sasaki Y . Upregulation of Flt3 expression within the bone marrow Lin(-)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity. Immunity. 2001; 15(4):659-69. DOI: 10.1016/s1074-7613(01)00220-5. View

18.

Kiel M, Yilmaz O, Iwashita T, Yilmaz O, Terhorst C, Morrison S . SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005; 121(7):1109-21. DOI: 10.1016/j.cell.2005.05.026. View

19.

Hwang M, Gorivodsky M, Kim M, Westphal H, Geum D . The neuronal differentiation potential of Ldb1-null mutant embryonic stem cells is dependent on extrinsic influences. Stem Cells. 2008; 26(6):1490-5. DOI: 10.1634/stemcells.2007-1099. View

20.

Landry J, Bonadies N, Kinston S, Knezevic K, Wilson N, Oram S . Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors. Blood. 2009; 113(23):5783-92. DOI: 10.1182/blood-2008-11-187757. View