Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2.
Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by using the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (together referred to as OSKM). iPSC reprogramming erases somatic epigenetic signatures—as typified by DNA methylation or histone modification at silent pluripotency loci—and establishes alternative epigenetic marks of embryonic stem cells (ESCs). Here we describe an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as Nanog and Esrrb. By day 4 after transduction with OSKM, two epigenetic modification factors necessary for iPSC generation, namely poly(ADP-ribose) polymerase-1 (Parp1) and ten-eleven translocation-2 (Tet2), are recruited to the Nanog and Esrrb loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: Parp1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas Tet2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC (refs 3,4). Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts, our data, and also studies of Tet2-mutant human tumour cells, argue in favour of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, Parp1 and Tet2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas Parp1 induction further promotes accessibility to the Oct4 reprogramming factor. These findings suggest that Parp1 and Tet2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.
Department of Pathology, Taub Institute for Aging, Columbia University, New York, New York 10032, USA.
Claudia A
CA
Doege
Keiichi
K
Inoue
Toru
T
Yamashita
David B
DB
Rhee
Skylar
S
Travis
Ryousuke
R
Fujita
Paolo
P
Guarnieri
Govind
G
Bhagat
William B
WB
Vanti
Alan
A
Shih
Ross L
RL
Levine
Sara
S
Nik
Emily I
EI
Chen
Asa
A
Abeliovich
D000818:Animals; D065150:Cellular Reprogramming; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D007438:Introns / Q000235:genetics; D000090062:Kruppel-Like Factor 4; D051379:Mice; D000071317:Nanog Homeobox Protein; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism
D002843:Chromatin; D004268:DNA-Binding Proteins; C098925:Esrrb protein, mouse; D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D049308:Dioxygenases; C541081:TET2 protein, human; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases