Histone deacetylases 1 and 2 regulate the transcriptional programs of nephron progenitors and renal vesicles

Abstract

Nephron progenitor cells (NPC) are Six2-positive metanephric mesenchyme cells, which undergo self-renewal and differentiation to give rise to nephrons until the end of nephrogenesis. HDACs are a group of epigenetic regulators that control cell fate but their role in balancing NPC renewal and differentiation is unknown. Here, we report that NPC-specific deletion of HDAC1 and HDAC2 genes in mice results in early postnatal lethality due to renal hypo-dysplasia and loss of NPC. HDAC1/2 interact with the NPC renewal regulators Six2, Osr1 and Sall1, and are co-bound along with Six2 on the Six2 enhancer. Although the mutant NPC differentiate into RV, HDAC1/2 mutant kidneys lack nascent nephrons or mature glomeruli, a phenocopy of Lhx1-mutants. Transcriptional profiling and network analysis identified disrupted expression of Lhx1 and its downstream genes Dll1 and Hnf1/4 as key mediators of the renal phenotype. Finally, although HDAC1/2-deficient NPC and RV overexpress hyperacetylated p53, Trp53 deletion failed to rescue the renal dysgenesis. We conclude that the epigenetic regulators, HDAC1 and HDAC2, control nephrogenesis via interactions with the transcriptional programs of nephron progenitors and renal vesicles.