Human RNA-Directed DNA Methylation Methylates High-Mobility Group Box 1 Protein-Produced DNA Gaps

Abstract

Background: DNA sequences around HMGB1-produced DNA gaps are hypermethylates. DNA methylation of interspersed repetitive sequences (IRS) such as Alu elements can be established through AGO4-mediating, RNA-directed DNA methylation (RdDM). HMGB1 depletion, DNA gap reduction and global hypomethylation promote genomic instability. Methods: 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. Results: 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. Conclusion: 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.

Keywords::

• AGO4
• Alu methylation
• Alu siRNA
• genomic instability
• global hypomethylation
• HMGB1
• human RNA-directed DNA methylation
• RdDM
• Youth-DNA-GAPs

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2022-0022

Author contributions

PW performed all experiments and wrote the manuscript. AM conceived and designed the study as well as wrote and edited the manuscript.

Financial & competing interests disclosure

This work was supported by the National Science and Technology Development Agency, Thailand [Research Chair Grant, P-19-50189] and the Chulalongkorn University 100th Year Birthday Anniversary Doctoral Degree Scholarship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by the National Science and Technology Development Agency, Thailand [Research Chair Grant, P-19-50189] and the Chulalongkorn University 100th Year Birthday Anniversary Doctoral Degree Scholarship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.