TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS.
TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine, an emerging dynamic epigenetic state of DNA that can influence transcription. Evidence has linked TET1 function to epigenetic repression complexes, yet mechanistic information, especially for the TET2 and TET3 proteins, remains limited. Here, we show a direct interaction of TET2 and TET3 with O-GlcNAc transferase (OGT). OGT does not appear to influence hmC activity, rather TET2 and TET3 promote OGT activity. TET2/3-OGT co-localize on chromatin at active promoters enriched for H3K4me3 and reduction of either TET2/3 or OGT activity results in a direct decrease in H3K4me3 and concomitant decreased transcription. Further, we show that Host Cell Factor 1 (HCF1), a component of the H3K4 methyltransferase SET1/COMPASS complex, is a specific GlcNAcylation target of TET2/3-OGT, and modification of HCF1 is important for the integrity of SET1/COMPASS. Additionally, we find both TET proteins and OGT activity promote binding of the SET1/COMPASS H3K4 methyltransferase, SETD1A, to chromatin. Finally, studies in Tet2 knockout mouse bone marrow tissue extend and support the data as decreases are observed of global GlcNAcylation and also of H3K4me3, notably at several key regulators of haematopoiesis. Together, our results unveil a step-wise model, involving TET-OGT interactions, promotion of GlcNAcylation, and influence on H3K4me3 via SET1/COMPASS, highlighting a novel means by which TETs may induce transcriptional activation.
Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
Rachel
R
Deplus
Benjamin
B
Delatte
Marie K
MK
Schwinn
Matthieu
M
Defrance
Jacqui
J
Méndez
Nancy
N
Murphy
Mark A
MA
Dawson
Michael
M
Volkmar
Pascale
P
Putmans
Emilie
E
Calonne
Alan H
AH
Shih
Ross L
RL
Levine
Olivier
O
Bernard
Thomas
T
Mercher
Eric
E
Solary
Marjeta
M
Urh
Danette L
DL
Daniels
François
F
Fuks
D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006031:Glycosylation; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D051863:Host Cell Factor C1 / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; D006657:Histones; D051863:Host Cell Factor C1; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; C578792:TET3 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase