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

Abstract

Nephron progenitor cells (NPCs) are Six2-positive metanephric mesenchyme cells, which undergo self-renewal and differentiation to give rise to nephrons until the end of nephrogenesis. Histone deacetylases (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 <i>Hdac1</i> and <i>Hdac2</i> genes in mice results in early postnatal lethality owing to renal hypodysplasia and loss of NPCs. HDAC1/2 interact with the NPC renewal regulators Six2, Osr1 and Sall1, and are co-bound along with Six2 on the <i>Six2</i> enhancer. Although the mutant NPCs differentiate into renal vesicles (RVs), <i>Hdac1/2</i> mutant kidneys lack nascent nephrons or mature glomeruli, a phenocopy of <i>Lhx1</i> mutants. Transcriptional profiling and network analysis identified disrupted expression of <i>Lhx1</i> and its downstream genes, <i>Dll1</i> and <i>Hnf1a/4a</i>, as key mediators of the renal phenotype. Finally, although HDAC1/2-deficient NPCs and RVs overexpress hyperacetylated p53, <i>Trp53</i> 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.