| 研究実績の概要 |
By supporting from this start-up grant, I identified the crucial mechanism of erythropoiesis initiation from hematopoietic stem and progenitor cells (HSPCs). By generating several lines of Gata1 bacterial artificial chromosome transgenic mice in which the HSPC specific silencer was deleted, I could be able to induce high level of Gata1 or CreERT2 expression in HSPCs. By using these mouse models as well as Dnmt1 conditional knockout allele, I found the demethylation of enhancers (which was methylated and repressed by the HSPC specific silencer) of erythroid master transcription factor GATA1, and therefore the gene activation, is the key of the initiation of red blood cell differentiation. Transcription factor GATA2 plays a key role in Gata1 gene activation in absence of silencer element.
The ectopic induction of Gata1 gene in HSPCs significantly drives erythropoiesis, and also induces HSPC apoptosis. The result was published as "Derepression of the DNA methylation machinery of Gata1 gene triggers the differentiation cue for erythropoiesis" in Molecular and Cellular Biology in 2017.
This study further opened several interesting proposal, for example, the possibility of GATA1 based leukemia stem cells treatment.
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