Novel posttranslational modification of UHRF1 and its biological relevance

Abstract

UHRF1 is known as a critical protein involved in epigenetic regulation, which can recognize histone codes, modify histone codes directly through ubiquitination and indirectly by recruitment of KHMTs, HATs and HDACs, and maintain DNA methylation. Earlier studies have shown that UHRF1 can also be modified by phosphorylation, ubiquitination and acetylation, and previous work done by Dr. Mia Xiaobin Hu in our group has shown that UHRF1 can interact and be acetylated by hMOF, a HAT which belongs to the MYST family, though little is known about the biological relevance for this modification. In this work, for the first time, our studies have shown that UHRF1 can be specifically acetylated by MOF but not by other HATs, and by Mass Spectrometry analysis, we identified that the lysine residues Lys667, Lys668 and Lys670 within the pre-RING linker region of UHRF1 are the major sites modified by MOF. More importantly, we have shown that MOF acetylates UHRF1 in the S phase and this acetylation is important for UHRF1’s stabilization and function in DNA methylation maintenance.

HP1α is another important epigenetic regulator which can recognize repressive histone codes H3K9me2/3 through its chromo domain and promote heterochromatin formation. Earlier studies in HP1 family revealed that they could be extensively modified by PTMs such as acetylation, phosphorylation, methylation, formylation, ubiquitination and sumoylation, indicating the existence of a set of ‘subcode’ within the histone code. Moreover, acetylation has been found as a unique modification in HP1α, not in HP1β or HP1γ, indicating that acetylation of HP1α might have unique biological functions. In this study, we identified MOF and p300 as novel acetyltransferases for HP1α, and demonstrated that MOF can acetylate HP1α on Lys40 and Lys42 in the chromo domain. Moreover, we have shown that the mutation of those two lysine residues to non-acetylated mimics results in decreased binding of HP1α to H3K9me3, suggesting that the acetylation of HP1α by MOF contributes to its binding to heterochromatin mark.

Those findings in our study revealed the existence of novel ‘subcode’ within the epigenetic regulators such as UHRF1 and HP1α, and the ‘subcode’ in turn contributes to their functions in epigenetic regulation, which contributes to our understanding of the crosstalks between the epigenetic codes and ‘subcodes’.