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CASZ1 induces skeletal muscle and rhabdomyosarcoma differentiation through a feed-forward loop with MYOD and MYOG.
Nature Communications ( IF 14.7 ) Pub Date : 2020-02-14 , DOI: 10.1038/s41467-020-14684-4
Zhihui Liu 1 , Xiyuan Zhang 1 , Haiyan Lei 1 , Norris Lam 1 , Sakereh Carter 1 , Oliver Yockey 1 , Max Xu 1 , Arnulfo Mendoza 1 , Edjay R Hernandez 1 , Jun S Wei 2 , Javed Khan 2 , Marielle E Yohe 1 , Jack F Shern 1 , Carol J Thiele 1
Affiliation  

Embryonal rhabdomyosarcoma (ERMS) is a childhood cancer that expresses myogenic master regulatory factor MYOD but fails to differentiate. Here, we show that the zinc finger transcription factor CASZ1 up-regulates MYOD signature genes and induces skeletal muscle differentiation in normal myoblasts and ERMS. The oncogenic activation of the RAS-MEK pathway suppresses CASZ1 expression in ERMS. ChIP-seq, ATAC-seq and RNA-seq experiments reveal that CASZ1 directly up-regulates skeletal muscle genes and represses non-muscle genes through affecting regional epigenetic modifications, chromatin accessibility and super-enhancer establishment. Next generation sequencing of primary RMS tumors identified a single nucleotide variant in the CASZ1 coding region that potentially contributes to ERMS tumorigenesis. Taken together, loss of CASZ1 activity, due to RAS-MEK signaling or genetic alteration, impairs ERMS differentiation, contributing to RMS tumorigenesis.

中文翻译:


CASZ1 通过 MYOD 和 MYOG 的前馈循环诱导骨骼肌和横纹肌肉瘤分化。



胚胎性横纹肌肉瘤 (ERMS) 是一种表达肌源性主调节因子 MYOD 但无法分化的儿童癌症。在这里,我们发现锌指转录因子 CASZ1 上调 MYOD 特征基因并诱导正常成肌细胞和 ERMS 中的骨骼肌分化。 RAS-MEK 通路的致癌激活抑制 ERMS 中 CASZ1 的表达。 ChIP-seq、ATAC-seq 和 RNA-seq 实验表明,CASZ1 通过影响区域表观遗传修饰、染色质可及性和超级增强子建立,直接上调骨骼肌基因并抑制非肌肉基因。原发性 RMS 肿瘤的下一代测序鉴定出 CASZ1 编码区中的一个单核苷酸变异,该变异可能有助于 ERMS 肿瘤的发生。总而言之,由于 RAS-MEK 信号传导或基因改变而导致 CASZ1 活性丧失,会损害 ERMS 分化,从而导致 RMS 肿瘤发生。
更新日期:2020-02-14
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