Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome

被引：36

作者：

Hewitt, Kyle J. ^{[1
,2
]}

Kim, Duk Hyoung ^{[3
,4
]}

Devadas, Prithvia ^{[1
,2
]}

Prathibha, Rajalekshmi ^{[1
,2
]}

Zuo, Chandler ^{[5
]}

Sanalkumar, Rajendran ^{[1
,2
]}

Johnson, Kirby D. ^{[1
,2
]}

Kang, Yoon-A. ^{[1
,2
]}

Kim, Jin-Soo ^{[3
,4
]}

Dewey, Colin N. ^{[5
]}

Keles, Sunduz ^{[5
]}

Bresnick, Emery H. ^{[1
,2
]}

机构：

[1] Univ Wisconsin, Sch Med & Publ Hlth, Carbone Canc Ctr, Dept Cell & Regenerat Biol, Madison, WI 53705 USA

[2] UW Madison Blood Res Program, Madison, WI 53706 USA

[3] Seoul Natl Univ, Inst Basic Sci, Seoul 151742, South Korea

[4] Seoul Natl Univ, Dept Chem, Seoul 151742, South Korea

[5] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biostat & Med Informat, Madison, WI 53705 USA

来源：

MOLECULAR CELL | 2015年 / 59卷 / 01期

关键词：

GENOME-WIDE ANALYSIS; GATA FACTOR FUNCTION; TRANSCRIPTIONAL CONTROL; DNA ELEMENTS; CIS-ELEMENT; PROTEIN; STEM; KIT; SPINOPHILIN; MOUSE;

D O I：

10.1016/j.molcel.2015.05.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：62 / 74

页数：13

共 64 条

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