Molecular integration of HoxB4 and STAT3 for self-renewal of hematopoietic stem cells: a model of molecular convergence for stemness.
The upregulation of HoxB4 promotes self-renewal of hematopoietic stem cells (HSCs) without overriding the normal stem cell pool size. A similar enhancement of HSC self-renewal occurs when signal transducer and activator of transcription 3 (STAT3) is activated in HSCs. In this study, to gain insight into the functional organization of individual transcription factors (TFs) that have similar effects on HSCs, we investigated the molecular interplay between HoxB4 and STAT3 in the regulation of HSC self-renewal. We found that while STAT3-C or HoxB4 similarly enhanced the in vitro self-renewal and in vivo repopulating activities of HSCs, simultaneous transduction of both TFs did not have additive effects, indicating their functional redundancy in HSCs. In addition, activation of STAT3 did not cause changes in the expression levels of HoxB4. In contrast, the inhibition of STAT3 activity in HoxB4-overexpressing hematopoietic cells significantly abrogated the enhancing effects of HoxB4, and the upregulation of HoxB4 caused a ligand-independent Tyr-phosphorylation of STAT3. Microarray analysis revealed a significant overlap of the transcriptomes regulated by STAT3 and HoxB4 in undifferentiated hematopoietic cells. Moreover, a gene set enrichment analysis showed significant overlap in the candidate TFs that can recapitulate the transcriptional changes induced by HoxB4 or STAT3. Interestingly, among these common TFs were the pluripotency-related genes Oct-4 and Nanog. These results indicate that tissue-specific TFs regulating HSC self-renewal are functionally organized to play an equivalent role in transcription and provide insights into the functional convergence of multiple entries of TFs toward a conserved transcription program for the stem cell state.
Catholic High-Performance Cell Therapy Center and Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Sung-Hyun
SH
Hong
Seung-Jip
SJ
Yang
Tae-Min
TM
Kim
Jae-Seung
JS
Shim
Ho-Sun
HS
Lee
Ga-Young
GY
Lee
Bo-Bae
BB
Park
Suk Woo
SW
Nam
Zae Young
ZY
Ryoo
Il-Hoan
IH
Oh
D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014157:Transcription Factors; D014443:Tyrosine
Hematopoietic stem cell; HoxB4; Self-renewal