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Satb1 regulates the self-renewal of hematopoietic stem cells by promoting quiescence and repressing differentiation commitment

Nature Immunology volume 14, pages 437–445 (2013)Cite this article

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Abstract

How hematopoietic stem cells (HSCs) coordinate the regulation of opposing cellular mechanisms such as self-renewal and differentiation commitment remains unclear. Here we identified the transcription factor and chromatin remodeler Satb1 as a critical regulator of HSC fate. HSCs lacking Satb1 had defective self-renewal, were less quiescent and showed accelerated lineage commitment, which resulted in progressive depletion of functional HSCs. The enhanced commitment was caused by less symmetric self-renewal and more symmetric differentiation divisions of Satb1-deficient HSCs. Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc, which encode two key factors for the specification of stem-cell fate. Thus, Satb1 is a regulator that promotes HSC quiescence and represses lineage commitment.

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Figure 1: Satb1 is expressed in HSCs and is critical for the long-term–repopulation ability of HSCs.
Figure 2: Satb1 deficiency leads to less HSC quiescence.
Figure 3: Satb1 deficiency results in the generation of more MPPs and colony-initiating cells from the HSC compartment.
Figure 4: Satb1−/− HSCs show greater differentiation commitment, a loss of symmetric self-renewal and more symmetric differentiation divisions.
Figure 5: Inhibition of enhanced c-Myc activity restores the enhanced differentiation commitment of Satb1−/− HSCs to wild-type rates.
Figure 6: Epigenetic alterations in Satb1−/− HSCs.

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Acknowledgements

We thank T. Kohwi-Shigematsu (Lawrence Berkeley National Laboratory) for Satb1−/− mice; J. Bradner (Dana-Farber Cancer Institute, Harvard Medical School) for JQ1; T. Kohwi-Shigematsu, E. Passegué, M. Alberich-Jordá and the members of the Steidl laboratory for discussions and suggestions; G. Simkin, and S. Narayanagari of the Einstein Human Stem Cell FACS and Xenotransplantation Facility; and P. Schultes, C. Sheridan and the Epigenomics Core Facility of Weill Cornell Medical College for technical assistance. Supported by the American Cancer Society (121366-PF-12-89-01-TBG to B.W.), the Sass Foundation (F.G.B.), the National Cancer Institute (1K08CA169055-01 to F.G.B. and R00CA131503 to U.S.), the US National Institutes of Health (F31CA162770 to U.C.O.-O. and F30HL117545 to A.P.) and New York State Stem Cell Science (C024306, C026416 and C028116 to U.S., and C024172 to E. Bouhassira). U.S. is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research of the Albert Einstein College of Medicine.

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Authors and Affiliations

  1. Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA

    Britta Will, Thomas O Vogler, Boris Bartholdy, Jillian Mayer, Laura Barreyro, Ashley Pandolfi, Tihomira I Todorova, Ujunwa C Okoye-Okafor, Robert F Stanley, Michael Roth & Ulrich Steidl

  2. Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA

    Britta Will, Amit Verma & Ulrich Steidl

  3. Department of Medicine, Weill Cornell Medical College, New York, New York, USA

    Francine Garrett-Bakelman & Ari Melnick

  4. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA

    Tushar D Bhagat & Amit Verma

  5. Department of Medicine (Oncology), Albert Einstein College of Medicine, Bronx, New York, USA

    Amit Verma & Ulrich Steidl

  6. Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, USA

    Amit Verma & Ulrich Steidl

  7. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Maria E Figueroa

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Contributions

B.W. and U.S. designed the study and experiments; B.W., T.O.V., F.G.-B., T.D.B., J.M. and T.I.T. did experiments; B.W., T.O.V., J.M., B.B., F.G.-B., A.P., L.B., U.C.O.-O., R.F.S., T.I.T., M.R., A.V., M.E.F., A.M. and U.S. interpreted experiments; B.B. and L.B. did statistical analysis of microarray data; B.B. and F.G.-B. did statistical analysis of ERRBS data; and B.W. and U.S. wrote the manuscript.

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Correspondence to Ulrich Steidl.

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Will, B., Vogler, T., Bartholdy, B. et al. Satb1 regulates the self-renewal of hematopoietic stem cells by promoting quiescence and repressing differentiation commitment. Nat Immunol 14, 437–445 (2013). https://doi.org/10.1038/ni.2572

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