PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands Journal Article

Authors: Wang, X.; Rosikiewicz, W.; Sedkov, Y.; Martinez, T.; Hansen, B. S.; Schreiner, P.; Christensen, J.; Xu, B.; Pruett-Miller, S. M.; Helin, K.; Herz, H. M.
Article Title: PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands
Abstract: DNAmethylation at enhancers and CpG islands usually leads to gene repression,which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2, the glycosyltransferase OGT and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. In addition, PROSER1, UTX, TET1/2, and OGT colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, TET1/2, and OGT at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional down-regulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Furthermore, we provide evidence that PROSER1 acts as a more general regulator of OGT activity by controlling O-GlcNAcylation of multiple other chromatin signaling pathways. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands and supports an important role for PROSER1 in regulating the function of various chromatin-associated proteins via OGT-mediated O-GlcNAcylation. © 2022 Rockefeller University Press. All rights reserved.
Journal Title: Life Science Alliance
Volume: 5
Issue: 1
ISSN: 2575-1077
Publisher: Rockefeller University Press  
Date Published: 2022-01-01
Start Page: e202101228
Language: English
DOI: 10.26508/lsa.202101228
PROVIDER: scopus
PMCID: PMC8548262
PUBMED: 34667079
Notes: Article -- Export Date: 1 December 2021 -- Source: Scopus
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MSK Authors
  1. Kristian Helin
    19 Helin