Increase in DNA Damage by MYCN Knockdown Through Regulating Nucleosome Organization and Chromatin State in Neuroblastoma

摘要

As a transcription factor, MYCN regulates myriad target genes including the histone chaperone FACT. Moreover, FACT and MYCN expression form a forward feedback loop in neuroblastoma. It is unclear whether MYCN is involved in chromatin remodeling in neuroblastoma through regulation of its target genes. We showed here that MYCN knockdown resulted in loss of the nucleosome-free regions through nucleosome assembly in the promoters of genes functionally enriched for DNA repair. The active mark H3K9ac was removed or replaced by the repressive mark H3K27me3 in the promoters of double-strand break repair-related genes upon MYCN knockdown. Such chromatin state alterations occurred only in MYCN-bound promoters. Consistently, MYCN knockdown resulted in a marked increase in DNA damage in the treatment with hydroxyurea. In contrast, nucleosome reorganization and histone modification changes in the enhancers largely included target genes with tumorigenesis-related functions such as cell proliferation, cell migration, and cell-cell adhesion. The chromatin state significantly changed in both MYCN-bound and MYCN-unbound enhancers upon MYCN knockdown. Furthermore, MYCN knockdown independently regulated chromatin remodeling in the promoters and the enhancers. These findings reveal the novel epigenetic regulatory role of MYCN in chromatin remodeling and provide an alternative potential epigenetic strategy for MYCN-driven neuroblastoma treatment.

出版物
FRONTIERS IN GENETICS
胡欣洁
胡欣洁
2012级硕士,2014年秋转博,2020年1月毕业
郑炜圣
郑炜圣
2012级硕士,2014年秋转博,2021年5月毕业
朱乾书
朱乾书
2015级硕士,2017年秋转博,2021年8月毕业,2021年9月入站博士后,2024年8月出站,现为重庆市妇幼保健院副研究员
顾靓
顾靓
2015级博士,实验室助理,2020年12月毕业,2021年1月入站博士后,2023年12月出站,现为上海市免疫学研究所助理教授
江赐忠
江赐忠
博士生导师;PI
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