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Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells

Nature Immunology volume 12, pages 129–136 (2011)Cite this article

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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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Figure 1: Ldb1 is required for hematopoietic specification but is not essential for ESC maintenance.
Figure 2: Ldb1−/− hematopoietic progenitors are present in chimeric fetal livers but are unable to reconstitute hematopoiesis in irradiated recipients.
Figure 3: Ldb1−/− fetal hematopoietic progenitor (LSK) populations do not contain LTR-HSCs.
Figure 4: Ldb1 is continuously required for the maintenance of adult HSCs.
Figure 5: Ldb1 regulates the expression of many transcription factors required for HSC maintenance.
Figure 6: Ldb1 complex–binding sites are present in a high percentage of genes critical for HSCs.

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Acknowledgements

We thank D. El-Khoury and A. Grinberg for technical support, and M. Mukhopadhyay for advice about mouse experiments. Supported by the Intramural Research Program of the National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development, L.L., J.Y.L., T.C., M.G., I.T., Y.Z., H.W. and P.E.L.; National Institute of Environmental Health Sciences, R.J.; National Heart, Lung, and Blood Institute, K.C. and K.Z.) and the National Institutes of Health (DK068634 to E.H.B.).

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Authors and Affiliations

  1. Section on Cellular & Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

    LiQi Li, Jan Y Lee & Paul E Love

  2. Biostatistics Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA

    Raja Jothi

  3. Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA

    Kairong Cui & Keji Zhao

  4. Section on Mammalian Molecular Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

    Tsadok Cohen, Marat Gorivodsky, Itai Tzchori, Yangu Zhao & Heiner Westphal

  5. Department of Microbiology & Immunology, State University of New York Upstate Medical University, Syracuse, New York, USA

    Sandra M Hayes

  6. Wisconsin Institutes for Medical Research, Paul Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

    Emery H Bresnick

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Contributions

L.L. designed and (with assistance from P.E.L.) did all of the experiments; L.L. and P.E.L. designed the study and wrote the manuscript; K.C. and K.Z. assisted in designing and doing the ChIP-Seq experiments; R.J. did the statistical analysis of ChIP-Seq data; E.H.B. provided reagents and input for the ChIP-Seq experiments; J.Y.L., T.C., M.G., I.T., Y.Z. and S.M.H. assisted with specific mouse experiments and provided input on experimental design; and H.W. provided the Ldb1 mouse strains.

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Correspondence to Paul E Love.

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Li, L., Jothi, R., Cui, K. et al. Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells. Nat Immunol 12, 129–136 (2011). https://doi.org/10.1038/ni.1978

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