多梳抑制复合物 2 蛋白 EZH1 和 EZH2 通过抑制具有常染色质启动子的基因来调节小鼠出生后肝细胞成熟和纤维化的时间。
Polycomb Repressive Complex 2 Proteins EZH1 and EZH2 Regulate Timing of Postnatal Hepatocyte Maturation and Fibrosis by Repressing Genes With Euchromatic Promoters in Mice.
机构信息
Institute for Regenerative Medicine, University of Pennsylvania, Smilow Center for Translational Research, Philadelphia, Pennsylvania; Penn Epigenetics Institute, University of Pennsylvania, Smilow Center for Translational Research, Philadelphia, Pennsylvania; Department of Cell and Developmental Biology, University of Pennsylvania, Smilow Center for Translational Research, Philadelphia, Pennsylvania; Department of Cancer Biology, University of Pennsylvania, Smilow Center for Translational Research, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Smilow Center for Translational Research, Philadelphia, Pennsylvania.
Institute for Regenerative Medicine, University of Pennsylvania, Smilow Center for Translational Research, Philadelphia, Pennsylvania; Penn Epigenetics Institute, University of Pennsylvania, Smilow Center for Translational Research, Philadelphia, Pennsylvania; Department of Cell and Developmental Biology, University of Pennsylvania, Smilow Center for Translational Research, Philadelphia, Pennsylvania.
出版信息
Gastroenterology. 2019 May;156(6):1834-1848. doi: 10.1053/j.gastro.2019.01.041. Epub 2019 Jan 25.
BACKGROUND & AIMS: Little is known about mechanisms that underlie postnatal hepatocyte maturation and fibrosis at the chromatin level. We investigated the transcription of genes involved in maturation and fibrosis in postnatal hepatocytes of mice, focusing on the chromatin compaction the roles of the Polycomb repressive complex 2 histone methyltransferases EZH1 and EZH2.
METHODS
Hepatocytes were isolated from mixed background C57BL/6J-C3H mice, as well as mice with liver-specific disruption of Ezh1 and/or Ezh2, at postnatal day 14 and 2 months after birth. Liver tissues were collected and analyzed by RNA sequencing, H3K27me3 chromatin immunoprecipitation sequencing, and sonication-resistant heterochromatin sequencing (a method to map heterochromatin and euchromatin). Liver damage was characterized by histologic analysis.
RESULTS
We found more than 3000 genes differentially expressed in hepatocytes during liver maturation from postnatal day 14 to month 2 after birth. Disruption of Ezh1 and Ezh2 in livers caused perinatal hepatocytes to differentiate prematurely and to express genes at postnatal day 14 that would normally be induced by month 2 and differentiate prematurely. Loss of Ezh1 and Ezh2 also resulted in liver fibrosis. Genes with H3K27me3-postive and H3K4me3-positive euchromatic promoters were prematurely induced in hepatocytes with loss of Ezh1 and Ezh2-these genes included those that regulate hepatocyte maturation, fibrosis, and genes not specifically associated with the liver lineage.
CONCLUSIONS
The Polycomb repressive complex 2 proteins EZH1 and EZH2 regulate genes that control hepatocyte maturation and fibrogenesis and genes not specifically associated with the liver lineage by acting at euchromatic promoter regions. EZH1 and EZH2 thereby promote liver homeostasis and prevent liver damage. Strategies to manipulate Polycomb proteins might be used to improve hepatocyte derivation protocols or developed for treatment of patients with liver fibrosis.
背景与目的
对于在染色质水平上支配出生后肝细胞成熟和纤维化的机制，人们知之甚少。我们在出生后 14 天和 2 个月的 C57BL/6J-C3H 混合背景小鼠以及肝脏特异性缺失 Ezh1 和/或 Ezh2 的小鼠的原代肝细胞中，研究了参与成熟和纤维化的基因的转录，重点研究了染色质凝聚和 Polycomb 抑制复合物 2 组蛋白甲基转移酶 EZH1 和 EZH2 的作用。
方法
从小鼠中分离出生后 14 天和 2 个月的原代肝细胞，以及肝脏特异性缺失 Ezh1 和/或 Ezh2 的小鼠的原代肝细胞。通过 RNA 测序、H3K27me3 染色质免疫沉淀测序和超声处理抗性异染色质测序（一种绘制异染色质和常染色质的方法）分析肝组织。通过组织学分析来描述肝损伤。
结果
我们发现，从出生后 14 天到 2 个月的肝成熟过程中，肝细胞中有 3000 多个基因表达差异。Ezh1 和 Ezh2 在肝脏中的缺失导致围产期肝细胞过早分化，并在出生后 14 天表达通常在 2 个月后诱导分化的基因。Ezh1 和 Ezh2 的缺失也导致了肝纤维化。在 Ezh1 和 Ezh2 缺失的肝细胞中，具有 H3K27me3 阳性和 H3K4me3 阳性常染色质启动子的基因过早诱导-这些基因包括调节肝细胞成熟、纤维化以及与肝谱系无关的基因。
结论
Polycomb 抑制复合物 2 蛋白 EZH1 和 EZH2 通过作用于常染色质启动子区域，调节控制肝细胞成熟和纤维化以及与肝谱系无关的基因的表达。EZH1 和 EZH2 从而促进肝脏的内稳态并防止肝损伤。操纵 Polycomb 蛋白的策略可能被用于改进肝细胞衍生方案，或开发用于治疗肝纤维化的患者。
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