Figure 7. Model of PROSER1 function at enhancers and CpG islands and broader implication for PROSER1 as a general mediator of OGT activity in chromatin signaling.

(A) Model of PROSER1 function at enhancers and CpG islands. PROSER1 mediates OGT interaction with and O-GlcNAcylation of TET2 to control TET2 stabilization at enhancers and CGIs that are controlled by the activity of the MLL3/4 complexes. TET2 is involved in the recruitment of the MLL3/4 complexes via their complex-specific subunit UTX. In the absence of PROSER1 TET2 stabilization at enhancers and CGIs is impaired resulting in reduced recruitment of the MLL3/4 complexes. TF, transcription factor. (B) Western blot of IP with an O-GlcNAc–specific antibody from WT and PROSER1 KO HEK293 cells confirming strongly reduced O-GlcNAcylation of TET2 in PROSER1 KO compared with WT cells. Nuclear extracts were used as input. Actin was used as a loading control for the inputs. (C) IP with an O-GlcNAc–specific antibody followed by mass spectrometry identifies TET1 and OGT as differentially O-GlcNAcylated in WT versus PROSER1 KO HEK293 cells. Many components of the H3K4 methyltransferase and demethylase family also display reduced O-GlcNAcylation in PROSER1 KO compared with WT cells. Of note, QSER1, a protein just recently described as a factor that protects DNA methylation valleys from de novo methylation also showed reduced O-GlcNAcylation in PROSER1 KO versus WT cells.