Transcriptional changes and epigenetic landscapes in fetal hematopoietic stem and progenitor cells with DDX21 knockout
Fetal hematopoietic stem cells and their committed progenitors (HSPCs) are highly proliferative cells that rely on active ribosome biogenesis to support their rapid expansion during fetal hematopoiesis. Insufficient ribosome biogenesis, a pathological condition known as ribosomopathy, activates the p53 pathway and induces cell cycle arrest in immature progenitor cells, leading to disrupted hematopoiesis and erythroid aplasia (anemia). DDX21 is an RNA helicase that regulates ribosome biogenesis by modulating rRNA splicing, processing, and ribosomal protein transcription. To elucidate the role of DDX21 in hematopoiesis, we generated Ddx21 conditional knockout (Ddx21cKO) in hematopoietic cells by crossing Ddx21f/f with Vav1-Cre mice. The Ddx21cKO embryos showed defective hematopoiesis and decreased HSPC numbers and their committed progenitors (CMP, GMP, and MEP). In this study, transcriptional changes in E13.5 HSPCs were analyzed by RNA-seq. Epigenetic marks associated active chromatin (H3K4me3, H3K27ac) and repressive chromatin (H3K27me3, H4K4me1) were analyzed by CUT&amp;Tag. Chromatin accessibility was analyzed by ATAC-seq, whereas chromatin occupancies by Ddx21 and Kdm5a were analyzed by CUT&amp;Tag.