Cleavage stimulating factor 64 depletion mitigates cardiac fibrosis through alternative polyadenylation.
Cleavage stimulating factor 64 depletion mitigates cardiac fibrosis through alternative polyadenylation.
复制标题
裂解刺激因子64耗竭可通过替代聚腺苷酸化来减轻心脏纤维化。
DOI：
10.1016/j.bbrc.2022.01.093
复制
发表时间：
2022-03-15
影响因子：
3.1
通讯作者：
Thandavarayan, Rajarajan A.
中科院分区：
文献类型：
--
作者：
Neupane, Rahul;Youker, Keith;Yalamanchili, Hari Krishna;Cieslik, Katarzyna A.;Karmouty-quintana, Harry;Guha, Ashrith;Thandavarayan, Rajarajan A.
选择性多聚腺苷化（APA）通过在3'UTR的不同多聚腺苷化位点（PAS）上切割和添加poly(A)序列来调控基因表达，从而产生不同长度的转录物异构体。劈裂刺激因子64 （CstF64）是一种APA调节因子，在PAS选择中起作用，并决定3'UTR的长度。CstF64倾向于使用近端PAS，导致3'UTR缩短，通过增加靶基因的稳定性来增强蛋白表达。本研究的目的是研究CstF64在心脏纤维化中的作用，心脏纤维化是导致心力衰竭（HF）的关键事件。我们通过计算心衰患者左心室（LV）组织和心脏成纤维细胞的远端PAS （dPAS）使用率，确定了CstF64、关键纤维化基因的表达及其3'UTR的变化。CstF64在HF - LV组织和心脏成纤维细胞中表达上调，COL1A和FN1等促纤维化基因沉积增加，其3'UTR明显缩短。此外，HF心肌成纤维细胞显示转化生长因子受体β1 （TGFβR1）表达增加，与TGFβR1显著缩短一致。在HF成纤维细胞中敲除CstF64后，观察到与3'UTR延长相关的促纤维化基因下调。我们的发现表明CstF64在心衰期间通过APA激活肌成纤维细胞和促进心脏纤维化中起重要作用。因此，靶向CstF64介导的RNA加工方法可以为限制纤维化重塑提供一种新的治疗策略。该模型说明CstF64上调对心脏纤维化的影响。
Alternative polyadenylation (APA) regulates gene expression by cleavage and addition of poly(A) sequence at different polyadenylation sites (PAS) in 3’UTR, thus, generating transcript isoforms with different lengths. Cleavage stimulating factor 64 (CstF64) is an APA regulator which plays a role in PAS selection and determines the length of 3’UTR. CstF64 favors the use of proximal PAS, resulting in 3’UTR shortening, which enhances the protein expression by increasing the stability of the target genes. The aim of this study is to investigate the role of CstF64 in cardiac fibrosis, a key event leading to heart failure (HF). We determined the expression of CstF64, key profibrotic genes, and their 3’UTR changes by calculating distal PAS (dPAS) usage in left ventricular (LV) tissues and cardiac fibroblasts from HF patients. CstF64 was upregulated in HF LV tissues and cardiac fibroblasts along with increased deposition of profibrotic genes such as COL1A and FN1 and significant shortening in their 3’UTR. In addition, HF cardiac fibroblasts showed increased transforming growth factor receptor β1 (TGFβR1) expression consistent with significant shortening in TGFβR1. Upon knockdown of CstF64 from HF fibroblasts, downregulation in profibrotic genes corresponding to lengthening in their 3’UTR was observed. Our finding suggests an important role of CstF64 in myofibroblast activation and promotion of cardiac fibrosis during HF through APA. Therefore, targeting CstF64 mediated RNA processing approach in human HF could provide a new therapeutic treatment strategy for limiting fibrotic remodeling. The model illustrates the effect of CstF64 upregulation on cardiac fibrosis.
登录
查看更多内容
CSTF复合体的重建揭示了CSTF-50在识别3'-End处理信号方面的调节作用。
影响因子：
14.9
作者：
Yang W;Hsu PL;Yang F;Song JE;Varani G
通讯作者：
Varani G
影响因子：
15.9
作者：
Weng, Tingting;Ko, Junsuk;Blackburn, Michael R.
通讯作者：
Blackburn, Michael R.
影响因子：
4
作者：
Murtha LA;Schuliga MJ;Mabotuwana NS;Hardy SA;Waters DW;Burgess JK;Knight DA;Boyle AJ
通讯作者：
Boyle AJ
影响因子：
16
作者：
Nam, Jin-Wu;Rissland, Olivia S.;Koppstein, David;Abreu-Goodger, Cei;Jan, Calvin H.;Agarwal, Vikram;Yildirim, Muhammed A.;Rodriguez, Antony;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
20.1
作者：
Gibb AA;Lazaropoulos MP;Elrod JW
通讯作者：
Elrod JW