Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome

Kyle J. Hewitt, Duk Hyoung Kim, Prithvia Devadas, Rajalekshmi Prathibha, Chandler Zuo, Rajendran Sanalkumar, Kirby D. Johnson, Yoon A. Kang, Jin Soo Kim, Colin N. Dewey, Sunduz Keles, Emery H. Bresnick

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Thousands of cis-elements in genomes are predicted to have vital functions. Although conservation, activity in surrogate assays, polymorphisms, and disease mutations provide functional clues, deletion from endogenous loci constitutes the gold-standard test. A GATA-2-binding, Gata2 intronic cis-element (+9.5) required for hematopoietic stem cell genesis in mice is mutated in a human immunodeficiency syndrome. Because+9.5 is the only cis-element known to mediate stem cell genesis, we devised a strategy to identify functionally comparable enhancers ("+9.5-like") genome-wide. Gene editing revealed+9.5-like activity to mediate GATA-2 occupancy, chromatin opening, and transcriptional activation. A+9.5-like element resided in Samd14, which encodes a protein of unknown function. Samd14 increased hematopoietic progenitor levels/activity and promoted signaling by a pathway vital for hematopoietic stem/progenitor cell regulation (stem cell factor/c-Kit), and c-Kit rescued Samd14 loss-of-function phenotypes. Thus, the hematopoietic stem/progenitor cell cistrome revealed a mediator of a signaling pathway that has broad importance for stem/progenitor cell biology.

Original languageEnglish (US)
Pages (from-to)62-74
Number of pages13
JournalMolecular Cell
Volume59
Issue number1
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Hewitt, K. J., Kim, D. H., Devadas, P., Prathibha, R., Zuo, C., Sanalkumar, R., Johnson, K. D., Kang, Y. A., Kim, J. S., Dewey, C. N., Keles, S., & Bresnick, E. H. (2015). Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome. Molecular Cell, 59(1), 62-74. https://doi.org/10.1016/j.molcel.2015.05.020