TY - JOUR
T1 - Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome
AU - Hewitt, Kyle J.
AU - Kim, Duk Hyoung
AU - Devadas, Prithvia
AU - Prathibha, Rajalekshmi
AU - Zuo, Chandler
AU - Sanalkumar, Rajendran
AU - Johnson, Kirby D.
AU - Kang, Yoon A.
AU - Kim, Jin Soo
AU - Dewey, Colin N.
AU - Keles, Sunduz
AU - Bresnick, Emery H.
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84937162292
U2 - 10.1016/j.molcel.2015.05.020
DO - 10.1016/j.molcel.2015.05.020
M3 - Article
C2 - 26073540
AN - SCOPUS:84937162292
SN - 1097-2765
VL - 59
SP - 62
EP - 74
JO - Molecular cell
JF - Molecular cell
IS - 1
ER -