From, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA

Will give a seminar entitled:

Dissecting metabolic gene regulatory networks in hematopoiesis

Abstract

Understanding the mechanisms governing hematopoiesis is critical for directed differentiation approaches of hematopoietic stem cells into mature blood lineages. In vivo models are ideally suited to study the complexity of this process, as hematopoiesis depends on both cell-autonomous and niche contributions. Generally, transcription and metabolism both influence cell function yet it is unknown how transcription controls metabolic pathways to specify cell fates. I will cover our recent work on how a metabolic program and consequently the epigenetic landscape is directly instructed by a lineage transcription factor to drive early erythroid differentiation. In a high-content chemical suppressor screen in bloodless mutant zebrafish embryos as an anemia model I identified inhibitors of the essential pyrimidine do novo synthesis enzyme dihydroorotate dehydrogenase (DHODH) to rescue erythropoiesis. The effect of DHODH inhibition in the rescued blood lineage can be explained by its functional link to coenzyme Q activity and mitochondrial respiration, which we show are essential for early lineage differentiation. I will discuss these results in the broader context of transcriptional regulation of developmental hematopoiesis.