Histone chaperone HIRA in regulation of transcription factor RUNX1 [Developmental Biology]

April 6th, 2015 by Majumder, A., Mohieddin, S. K., Joseph, S., Scambler, P. J., Dutta, D.

Runt-related transcription factor 1 (RUNX1) is indispensable for the generation of hemogenic endothelium. However, the regulation of RUNX1 during this developmental process is poorly understood. We investigated the role of the histone chaperone HIRA (histone cell cycle regulation-defective homolog A) from this perspective and report that HIRA significantly contributes towards the regulation of RUNX1 in the transition of differentiating mouse embryonic stem cells (ESCs) from hemogenic to hematopoietic stage. Direct interaction of HIRA and RUNX1 activates the downstream targets of RUNX1 implicated in generation of hematopoietic stem cells. At the molecular level, HIRA mediated incorporation of Histone H3.3 variant within the Runx1 +24 mouse conserved non-coding element is essential for the expression of Runx1 during endothelial-to-hematopoietic transition. An inactive chromatin at the intronic enhancer of Runx1 in absence of HIRA, significantly repressed the transition of cells from hemogenic to hematopoietic fate. We expect that the HIRA-RUNX1 axis might open up a novel approach in understanding leukemogenesis in future.