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Blood, Aug 05 2024, blood.2024023963 | https://doi.org/10.1182/blood.2024023963
CDK9 phosphorylates RUNX1 to promote megakaryocytic fate in megakaryocytic-erythroid progenitors
Nayoung Kwon 1, Yi-Chien Lu 2, Evrett N Thompson 3, Rubia Isler Mancuso 1, Lin Wang 4, Ping-Xia Zhang 5, Diane S Krause 2
1Yale University, New Haven, Connecticut, United States.
2Yale University School of Medicine, New Haven, Connecticut, United States.
3Yale University Department of Cell Biology, New Haven, Connecticut, United States.
4Yale University, new haven, United States.
5yale university, new haven, Connecticut, United States.
*Corresponding Author : Diane S. Krause
Abstract
The specification of megakaryocytic (Mk) or erythroid (E) lineages from primary human megakaryocytic-erythroid progenitors (MEP) is crucial for hematopoietic homeostasis, yet the underlying mechanisms regulating fate specification remain elusive. In this study, we identify RUNX1 as a key modulator of gene expression during MEP fate specification. Overexpression of RUNX1 in primary human MEP promotes Mk specification, while pan-RUNX inhibition favors E specification. Although total RUNX1 levels do not differ between Mk progenitors (MkP) and E progenitors (ErP), there are higher levels of serine-phosphorylated RUNX1 in MkP than ErP, and mutant RUNX1 with phospho-serine/threonine mimetic mutations (RUNX1-4D) significantly enhances the functional efficacy of RUNX1. To model the effects of RUNX1 variants, we employ human erythroleukemia (HEL) cell lines expressing wild-type (WT), phosphomimetic (RUNX1-4D), and non-phosphorylatable (RUNX1-4A) mutants showing that the three forms of RUNX1 differentially regulate expression of 2,625 genes. Both WT and RUNX1-4D variants increase expression in 40%, and decrease expression in another 40%, with lesser effects of RUNX1-4A. We find a significant overlap between the upregulated genes in WT and RUNX1-4D-expressing HEL cells and those upregulated in primary human MkP versus MEP. While inhibition of known RUNX1 serine/threonine kinases does not affect phosphoserine RUNX1 levels in primary MEP, specific inhibition of CDK9 in MEP leads to both decreased RUNX1 phosphorylation and increased erythroid commitment. Collectively, our findings show that serine/threonine phosphorylation of RUNX1 promotes Mk fate specification and introduce a novel kinase for RUNX1 linking the fundamental transcriptional machinery with activation of a cell-type specific transcription factor.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-09)
- 국외 연구진
- 생명과학 > 유전자발현
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