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.
journal_name
Mol Celljournal_title
Molecular cellauthors
Hewitt KJ,Kim DH,Devadas P,Prathibha R,Zuo C,Sanalkumar R,Johnson KD,Kang YA,Kim JS,Dewey CN,Keles S,Bresnick EHdoi
10.1016/j.molcel.2015.05.020subject
Has Abstractpub_date
2015-07-02 00:00:00pages
62-74issue
1eissn
1097-2765issn
1097-4164pii
S1097-2765(15)00356-1journal_volume
59pub_type
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