Retroelement-mediated cis-regulation of embryonic hematopoiesis

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Summary The goal of this proposal is to test the hypothesis that the transcriptional program mediating the process by which endothelial cells in the embryo differentiate into hematopoietic stem and progenitor cells (HSPCs) is coordinately regulated by cis-acting regulatory sequences derived from retroelements. Retroelements are repetitive DNA sequences comprising approximately 50% of mouse and human genomes. The long terminal repeats (LTRs) of the retrotransposon family of retroelements function as enhancers, promoters, and polyadenylation signals for endogenous gene expression and are highly enriched for transcription factor binding sites (TFBS). We have identified families and specific subfamilies of retrotransposons that are more highly expressed in the small population of endothelial cells in the embryo that differentiate into HSPCs (hemogenic endothelial cells) than in non-hemogenic endothelial cells, and in particular give rise to progenitors with potent lymphoid potential. Some of these subfamilies of retrotransposons contain RUNX1 motifs in their LTRs, and we hypothesize that RUNX1 regulates HSPC differentiation from hemogenic endothelial cells through these LTRs. We will use long read sequencing technology and bioinformatics approaches adapted for the purpose of analyzing retroelements to map transcriptionally active retroelements based on their expression and chromatin configuration to specific genomic coordinates and determine if they activate genes involved in HSPC formation from hemogenic endothelial cells. We will also determine if the RUNX1 transcription factor regulates the activity of a subset of these LTRs.