RNA helicase Ddx21 safeguards fetal HSPC expansion by recruiting Kdm5a to epigenetically sustain ribosomal and hematopoietic gene transcription

Abstract

Fetal hematopoietic stem and progenitor cells (HSPCs) require active ribosome biogenesis to sustain their rapid proliferation, yet how non-structural ribosomal factors regulate this process remains unclear. Here, we identify the RNA helicase Ddx21 as a critical determinant of fetal hematopoiesis through its epigenetic role in maintaining active ribosomal transcription. Conditional knockout of Ddx21 in murine fetal hematopoietic cells resulted in severe anemia, fetal liver hypoplasia, and depletion of HSPCs, accompanied by erythroid maturation arrest. Mechanistically, Ddx21 deficiency disrupted ribosomal and hematopoietic gene expressions, impaired translational capacity, and activated p53 pathway, triggering cell cycle arrest and apoptosis. While p53 inhibition partially rescued proliferation defects, it failed to restore rRNA transcription, pointing to p53-independent mechanisms. Multi-omics profiling revealed that Ddx21 interacts with the histone demethylase Kdm5a, co-occupying active promoters marked by H3K4me3. Loss of Ddx21 diminished H3K4me3 levels at ribosomal DNA (rDNA) and hematopoietic genes such as cKit and Gata1, downregulating their transcription. Strikingly, Kdm5a inhibition restored rRNA expression and protein translation in Ddx21-deficient cells, and combined inhibition of Kdm5a and p53 cooperatively rescued HSPC function. These findings demonstrate a paradigm wherein Ddx21 couples ribosome biogenesis to epigenetic regulation by sequestering Kdm5a at active chromatin, thereby preserving transcriptional output essential for fetal hematopoietic expansion.