| First Author | Hewitt KJ | Year | 2015 |
| Journal | Mol Cell | Volume | 59 |
| Issue | 1 | Pages | 62-74 |
| PubMed ID | 26073540 | Mgi Jnum | J:226119 |
| Mgi Id | MGI:5695809 | Doi | 10.1016/j.molcel.2015.05.020 |
| Citation | Hewitt KJ, et al. (2015) Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome. Mol Cell 59(1):62-74 |
| abstractText | 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. |
