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.
['Hong|Sung-Hyun|SH|', 'Yang|Seung-Jip|SJ|', 'Kim|Tae-Min|TM|', 'Shim|Jae-Seung|JS|', 'Lee|Ho-Sun|HS|', 'Lee|Ga-Young|GY|', 'Park|Bo-Bae|BB|', 'Nam|Suk Woo|SW|', 'Ryoo|Zae Young|ZY|', 'Oh|Il-Hoan|IH|']
D000818:Animals D015153:Blotting, Western D001854:Bone Marrow Cells D049109:Cell Proliferation D020869:Gene Expression Profiling D006412:Hematopoietic Stem Cells D018398:Homeodomain Proteins D008810:Mice, Inbred C57BL D008957:Models, Genetic D020411:Oligonucleotide Array Sequence Analysis D010766:Phosphorylation D020133:Reverse Transcriptase Polymerase Chain Reaction D050796:STAT3 Transcription Factor D015398:Signal Transduction D014157:Transcription Factors D014443:Tyrosine
HoxB4 Self-renewal Hematopoietic stem cell