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Fibrogenic Activity of MECP2 Is Regulated by Phosphorylation in Hepatic Stellate Cells.
Gastroenterology ( IF 25.7 ) Pub Date : 2019-07-25 , DOI: 10.1053/j.gastro.2019.07.029
Eva Moran-Salvador 1 , Marina Garcia-Macia 1 , Ashwin Sivaharan 1 , Laura Sabater 1 , Marco Y W Zaki 1 , Fiona Oakley 1 , Amber Knox 1 , Agata Page 1 , Saimir Luli 1 , Jelena Mann 1 , Derek A Mann 1
Affiliation  

BACKGROUND & AIMS Methyl-CpG binding protein 2, MECP2, which binds to methylated regions of DNA to regulate transcription, is expressed by hepatic stellate cells (HSCs) and is required for development of liver fibrosis in mice. We investigated the effects of MECP2 deletion from HSCs on their transcriptome and of phosphorylation of MECP2 on HSC phenotype and liver fibrosis. METHODS We isolated HSCs from Mecp2-/y mice and wild-type (control) mice. HSCs were activated in culture and used in array analyses of messenger RNAs and long noncoding RNAs. Kyoto Encyclopedia of Genes and Genomes pathway analyses identified pathways regulated by MECP2. We studied mice that expressed a mutated form of Mecp2 that encodes the S80A substitution, MECP2S80, causing loss of MECP2 phosphorylation at serine 80. Liver fibrosis was induced in these mice by administration of carbon tetrachloride, and liver tissues and HSCs were collected and analyzed. RESULTS MECP2 deletion altered expression of 284 messenger RNAs and 244 long noncoding RNAs, including those that regulate DNA replication; are members of the minichromosome maintenance protein complex family; or encode CDC7, HAS2, DNA2 (a DNA helicase), or RPA2 (a protein that binds single-stranded DNA). We found that MECP2 regulates the DNA repair Fanconi anemia pathway in HSCs. Phosphorylation of MECP2S80 and its putative kinase, HAS2, were induced during transdifferentiation of HSCs. HSCs from MECP2S80 mice had reduced proliferation, and livers from these mice had reduced fibrosis after carbon tetrachloride administration. CONCLUSIONS In studies of mice with disruption of Mecp2 or that expressed a form of MECP2 that is not phosphorylated at S80, we found phosphorylation of MECP2 to be required for HSC proliferation and induction of fibrosis. In HSCs, MECP2 regulates expression of genes required for DNA replication and repair. Strategies to inhibit MECP2 phosphorylation at S80 might be developed for treatment of liver fibrosis.

中文翻译:

肝星状细胞中的磷酸化调节了MECP2的纤维化活性。

背景与目的甲基-CpG结合蛋白2(MECP2)与DNA的甲基化区域结合以调节转录,由肝星状细胞(HSC)表达,是小鼠肝纤维化发展所必需的。我们调查了HSCs的MECP2缺失对其转录组的影响以及MECP2的磷酸化对HSC表型和肝纤维化的影响。方法我们从Mecp2- / y小鼠和野生型(对照)小鼠中分离了HSC。HSC在培养中被激活,并用于信使RNA和长非编码RNA的阵列分析。京都基因与基因组百科全书通路分析确定了由MECP2调控的通路。我们研究了表达突变形式的Mecp2的小鼠,该突变体编码S80A取代MECP2S80,导致丝氨酸80缺失的MECP2磷酸化。通过给予四氯化碳在这些小鼠中诱发肝纤维化,并收集和分析肝组织和HSC。结果MECP2缺失改变了284个信使RNA和244个长非编码RNA的表达,包括那些调节DNA复制的RNA。是微染色体维持蛋白复合物家族的成员;或编码CDC7,HAS2,DNA2(DNA解旋酶)或RPA2(结合单链DNA的蛋白质)。我们发现,MECP2调节HSC中DNA修复Fanconi贫血的途径。在HSC的转分化过程中,诱导了MECP2S80及其推定的激酶HAS2的磷酸化。施用四氯化碳后,来自MECP2S80小鼠的HSC增殖减少,并且这些小鼠的肝脏纤维化减少。结论在对Mecp2破坏或表达某种形式的MECP2在S80时未磷酸化的小鼠的研究中,我们发现MESC2的磷酸化是HSC增殖和诱导纤维化所必需的。在HSC中,MECP2调节DNA复制和修复所需的基因的表达。可能会开发出在S80抑制MECP2磷酸化的策略来治疗肝纤维化。
更新日期:2019-11-18
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