The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine.
How embryonic stem cells (ESCs) commit to specific cell lineages and yield all cell types of a fully formed organism remains a major question. ESC differentiation is accompanied by large-scale histone and DNA modifications, but the relations between these epigenetic categories are not understood. Here we demonstrate the interplay between the histone deacetylase sirtuin 6 (SIRT6) and the ten-eleven translocation enzymes (TETs). SIRT6 targets acetylated histone H3 at Lys 9 and 56 (H3K9ac and H3K56ac), while TETs convert 5-methylcytosine into 5-hydroxymethylcytosine (5hmC). ESCs derived from Sirt6 knockout (S6KO) mice are skewed towards neuroectoderm development. This phenotype involves derepression of OCT4, SOX2 and NANOG, which causes an upregulation of TET-dependent production of 5hmC. Genome-wide analysis revealed neural genes marked with 5hmC in S6KO ESCs, thereby implicating TET enzymes in the neuroectoderm-skewed differentiation phenotype. We demonstrate that SIRT6 functions as a chromatin regulator safeguarding the balance between pluripotency and differentiation through Tet-mediated production of 5hmC.
1] The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
Jean-Pierre
JP
Etchegaray
La Jolla Institute for Allergy and Immunology, Sanford Consortium for Regenerative Medicine, UCSD Department of Pharmacology, UCSD Moores Cancer Center, La Jolla, California 92037, USA.
Lukas
L
Chavez
La Jolla Institute for Allergy and Immunology, Sanford Consortium for Regenerative Medicine, UCSD Department of Pharmacology, UCSD Moores Cancer Center, La Jolla, California 92037, USA.
Yun
Y
Huang
1] The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
Kenneth N
KN
Ross
1] The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
Jiho
J
Choi
1] The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
Barbara
B
Martinez-Pastor
1] The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
Ryan M
RM
Walsh
The Center for Regenerative Medicine (CReM), Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Cesar A
CA
Sommer
La Jolla Institute for Allergy and Immunology, Sanford Consortium for Regenerative Medicine, UCSD Department of Pharmacology, UCSD Moores Cancer Center, La Jolla, California 92037, USA.
Matthias
M
Lienhard
Broad Technology Labs (BTL), The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Adrianne
A
Gladden
1] The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
Sita
S
Kugel
Department of Human Biochemistry, Medical School, CEFyBO-UBA-CONICET, Buenos Aires, CP1121, Argentina.
Dafne M
DM
Silberman
1] The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
Sridhar
S
Ramaswamy
The Center for Regenerative Medicine (CReM), Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Gustavo
G
Mostoslavsky
1] The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA [3] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
Konrad
K
Hochedlinger
Broad Technology Labs (BTL), The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Alon
A
Goren
La Jolla Institute for Allergy and Immunology, Sanford Consortium for Regenerative Medicine, UCSD Department of Pharmacology, UCSD Moores Cancer Center, La Jolla, California 92037, USA.
Anjana
A
Rao
1] The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
Raul
R
Mostoslavsky
D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D053595:Embryonic Stem Cells / Q000201:enzymology* / Q000473:pathology / Q000637:transplantation; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000201:enzymology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D000071317:Nanog Homeobox Protein; D055495:Neurogenesis; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013724:Teratoma / Q000201:enzymology / Q000473:pathology; D014162:Transfection
D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D011518:Proto-Oncogene Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse; C501860:Sirt6 protein, mouse; C516592:SIRT6 protein, human; D037761:Sirtuins