Histone deacetylases 1 and 2 regulate the transcriptional programs of nephron progenitors and renal vesicles
Histone deacetylases 1 and 2 regulate the transcriptional programs of nephron progenitors and renal vesicles
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DOI：
10.1242/dev.153619
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发表时间：
2018-05-01
期刊：
影响因子：
4.6
通讯作者：
El-Dahr, Samir S.
中科院分区：
文献类型：
--
作者：
Liu, Hongbing;Chen, Shaowei;El-Dahr, Samir S.
肾元祖细胞（Nephron progenitor cells, npc）是six2阳性的后肾间质细胞，在肾发生结束前，这些细胞会自我更新和分化产生肾元。组蛋白去乙酰化酶（hdac）是一组控制细胞命运的表观遗传调节剂，但其在平衡鼻咽癌更新和分化中的作用尚不清楚。在这里，我们报道了小鼠中npc特异性缺失Hdac1和Hdac2基因会导致肾脏发育不良和npc丢失导致出生后早期死亡。HDAC1/2与NPC更新调节因子Six2、Osr1和Sall1相互作用，并与Six2增强子上的Six2共同结合。虽然突变的NPCs分化为肾小泡（RVs），但Hdac1/2突变的肾脏缺乏新生肾单位或成熟肾小球，这是Lhx1突变体的表型。转录谱分析和网络分析发现，Lhx1及其下游基因Dll1和Hnf1a/4a的表达中断是肾脏表型的关键介质。最后，尽管hdac1 /2缺陷的npc和RVs过度表达高乙酰化的p53，但Trp53缺失未能挽救肾发育不良。我们得出结论，表观遗传调控因子HDAC1和HDAC2通过与肾细胞祖细胞和肾小泡的转录程序相互作用来控制肾发生。
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 Hdac1 and Hdac2 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 Six2 enhancer. Although the mutant NPCs differentiate into renal vesicles (RVs), 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 Hnf1a/4a, as key mediators of the renal phenotype. Finally, although HDAC1/2-deficient NPCs and RVs 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.