Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease
Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease
复制标题
DOI：
10.1172/jci95946
复制
发表时间：
2018-01-02
影响因子：
15.9
通讯作者：
Advani, Andrew
中科院分区：
文献类型：
--
作者：
Majumder, Syamantak;Thieme, Karina;Advani, Andrew
组蛋白修饰控制正常发育和疾病期间去分化的命运决定。在这里，我们着手确定组蛋白的动态变化在多大程度上影响正常静止的成人肾小球足细胞的分化表型。为此，我们研究了足细胞中抑制组蛋白H3赖氨酸27三甲基化（H3K27me3）标记平衡改变的后果。阿霉素肾毒性和肾次全切除术（SNx）研究表明，足细胞中组蛋白甲基化酶EZH2的缺失降低了H3K27me3水平，并使小鼠对肾小球疾病敏感。H3K27me3富集于足细胞Notch配体Jag1的启动子区，EZH2抑制或敲低对Jag1的抑制促进足细胞去分化。相反，抑制含Jumonji C结构域的去甲基化酶Jmjd3和UTX增加足细胞H3K27me3含量，减轻阿霉素肾毒性、SNx和糖尿病患者的肾小球疾病。局灶节段性肾小球硬化或糖尿病肾病患者肾小球足细胞表现出H3K27me3减少和UTX含量升高。与人类疾病类似，抑制Jmjd3和UTX可减缓肾小球损伤小鼠的肾病进展，并降低H3K27me3水平。总之，这些发现表明，表面稳定的染色质修饰可以在静止细胞中动态调节，表观遗传重编程可以通过抑制发育途径的再激活来改善肾小球疾病的预后。
Histone protein modifications control fate determination during normal development and dedifferentiation during disease. Here, we set out to determine the extent to which dynamic changes to histones affect the differentiated phenotype of ordinarily quiescent adult glomerular podocytes. To do this, we examined the consequences of shifting the balance of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark in podocytes. Adriamycin nephrotoxicity and subtotal nephrectomy (SNx) studies indicated that deletion of the histone methylating enzyme EZH2 from podocytes decreased H3K27me3 levels and sensitized mice to glomerular disease. H3K27me3 was enriched at the promoter region of the Notch ligand Jag1 in podocytes, and derepression of Jag1 by EZH2 inhibition or knockdown facilitated podocyte dedifferentiation. Conversely, inhibition of the Jumonji C domain-containing demethylases Jmjd3 and UTX increased the H3K27me3 content of podocytes and attenuated glomerular disease in adriamycin nephrotoxicity, SNx, and diabetes. Podocytes in glomeruli from humans with focal segmental glomerulosclerosis or diabetic nephropathy exhibited diminished H3K27me3 and heightened UTX content. Analogous to human disease, inhibition of Jmjd3 and UTX abated nephropathy progression in mice with established glomerular injury and reduced H3K27me3 levels. Together, these findings indicate that ostensibly stable chromatin modifications can be dynamically regulated in quiescent cells and that epigenetic reprogramming can improve outcomes in glomerular disease by repressing the reactivation of developmental pathways.