GABP controls a critical transcription regulatory module that is essential for maintenance and differentiation of hematopoietic stem/progenitor cells.
Maintaining a steady pool of self-renewing hematopoietic stem cells (HSCs) is critical for sustained production of multiple blood lineages. Many transcription factors and molecules involved in chromatin and epigenetic modifications have been found to be critical for HSC self-renewal and differentiation; however, their interplay is less understood. The transcription factor GA binding protein (GABP), consisting of DNA-binding subunit GABPα and transactivating subunit GABPβ, is essential for lymphopoiesis as shown in our previous studies. Here we demonstrate cell-intrinsic, absolute dependence on GABPα for maintenance and differentiation of hematopoietic stem/progenitor cells. Through genome-wide mapping of GABPα binding and transcriptomic analysis of GABPα-deficient HSCs, we identified Zfx and Etv6 transcription factors and prosurvival Bcl-2 family members including Bcl-2, Bcl-X(L), and Mcl-1 as direct GABP target genes, underlying its pivotal role in HSC survival. GABP also directly regulates Foxo3 and Pten and hence sustains HSC quiescence. Furthermore, GABP activates transcription of DNA methyltransferases and histone acetylases including p300, contributing to regulation of HSC self-renewal and differentiation. These systematic analyses revealed a GABP-controlled gene regulatory module that programs multiple aspects of HSC biology. Our studies thus constitute a critical first step in decoding how transcription factors are orchestrated to regulate maintenance and multipotency of HSCs.
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Shuyang
S
Yu
Kairong
K
Cui
Raja
R
Jothi
Dong-Mei
DM
Zhao
Xuefang
X
Jing
Keji
K
Zhao
Hai-Hui
HH
Xue
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D051268:GA-Binding Protein Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055106:Genome-Wide Association Study; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051268:GA-Binding Protein Transcription Factor; D051741:Kruppel-Like Transcription Factors; D051059:PTEN Phosphohydrolase; D019253:Proto-Oncogene Proteins c-bcl-2; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C474033:FoxO3 protein, mouse; C495656:Gabpa protein, mouse; C062076:zinc finger protein, X-linked; C487757:Pten protein, mouse