SUMOylation enhances DNMT1 function to repress mega-intergenic RNAs and viral mimicry

Area of Science:

• Epigenetics and Gene Regulation
• Cancer Biology
• Virology

Background:

• DNA methyltransferase 1 (DNMT1) is vital for mammalian development and often altered in cancer.
• DNMT1's role in recruiting to hemimethylated DNA via UHRF1 is known, but its broader chromatin interactions and regulation are less understood.

Purpose of the Study:

• To investigate the broader chromatin occupancy and regulatory mechanisms of DNMT1.
• To understand the consequences of DNMT1 inhibition on gene expression and cellular responses.

Main Methods:

• Chromatin occupancy analysis of DNMT1.
• Selective catalytic inhibition of DNMT1.
• Analysis of gene expression and endogenous viral element reactivation.
• Investigation of RNF4's role in DNMT1 regulation via SUMOylation.

Main Results:

• DNMT1 preferentially binds unmethylated CpG islands of active genes via its CXXC domain.
• Catalytic inhibition causes DNMT1 redistribution to partially methylated regions, dependent on UHRF1 and RFTS.
• DNMT1 inhibition leads to global hypomethylation and reactivation of endogenous viral elements, including mintRNAs, inducing a viral mimicry response.
• RNF4 regulates DNMT1 activity by controlling SUMOylated DNMT1 levels, acting as a rheostat.

Conclusions:

• DNMT1's chromatin binding is mediated by its CXXC domain at active gene CpG islands.
• Sustained DNMT1 inhibition triggers a cell-intrinsic viral mimicry response through reactivation of endogenous viral elements.
• RNF4-mediated SUMOylation of DNMT1 is a critical regulatory mechanism that maintains DNA methylation and prevents viral mimicry.