Watcharanurak Papitchaya, Mutirangura Apiwat
Interdisciplinary Program of Biomedical Sciences, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand.
Department of Anatomy, Center of Excellence in Molecular Genetics of Cancer & Human Disease, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
Epigenomics. 2022 Jun;14(12):741-756. doi: 10.2217/epi-2022-0022. Epub 2022 Jun 28.
DNA sequences around HMGB1-produced DNA gaps are hypermethylates. DNA methylation of interspersed repetitive sequences (IRS) such as elements can be established through AGO4-mediating, RNA-directed DNA methylation (RdDM). HMGB1 depletion, DNA gap reduction and global hypomethylation promote genomic instability. HMGB1, SIRT1, AGO4 and DNA gap colocalizations were evaluated. Then, Alu methylation was analyzed in HMGB1-deficient or HMGB1-overexpressing cells and Alu siRNA-transfected HMGB1-deficient cells. HMGB1, SIRT1, AGO4 and DNA gap are colocalized in the nucleus. Moreover, HMGB1 or Alu siRNA increased Alu methylation, whereas Alu siRNA could not methylate HMGB1-deficient cells. AGO4 play a role in methylating DNA sequence around HMGB1-produced DNA gaps and localize DNA gap in IRS, and loss of intranuclear HMGB1 causes global hypomethylation.
HMGB1产生的DNA缺口周围的DNA序列发生高甲基化。散布重复序列（IRS）如元件的DNA甲基化可通过AGO4介导的RNA指导的DNA甲基化（RdDM）来建立。HMGB1缺失、DNA缺口减少和全基因组低甲基化会促进基因组不稳定。对HMGB1、SIRT1、AGO4和DNA缺口的共定位进行了评估。然后，在HMGB1缺陷或HMGB1过表达细胞以及转染了Alu siRNA的HMGB1缺陷细胞中分析了Alu甲基化情况。HMGB1、SIRT1、AGO4和DNA缺口在细胞核中共定位。此外，HMGB1或Alu siRNA增加了Alu甲基化，而Alu siRNA不能使HMGB1缺陷细胞发生甲基化。AGO4在HMGB1产生的DNA缺口周围的DNA序列甲基化以及IRS中DNA缺口的定位中发挥作用，核内HMGB1的缺失会导致全基因组低甲基化。
