Poly(ADP-ribosyl)ation acts in the DNA demethylation of mouse primordial germ cells also with DNA damage-independent roles.
Poly(ADP-ribosyl)ation regulates chromatin structure and transcription driving epigenetic events. In particular, Parp1 is able to directly influence DNA methylation patterns controlling transcription and activity of Dnmt1. Here, we show that ADP-ribose polymer levels and Parp1 expression are noticeably high in mouse primordial germ cells (PGCs) when the bulk of DNA demethylation occurs during germline epigenetic reprogramming in the embryo. Notably, Parp1 activity is stimulated in PGCs even before its participation in the DNA damage response associated with active DNA demethylation. We demonstrate that PARP inhibition impairs both genome-wide and locus-specific DNA methylation erasure in PGCs. Moreover, we evidence that impairment of PARP activity causes a significant reduction of expression of the gene coding for Tet1 hydroxylases involved in active DNA demethylation. Taken together these results demonstrate new and adjuvant roles of poly(ADP-ribosyl)ation during germline DNA demethylation and suggest its possible more general involvement in genome reprogramming.
Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
Fabio
F
Ciccarone
Francesca Gioia
FG
Klinger
Angela
A
Catizone
Roberta
R
Calabrese
Michele
M
Zampieri
Maria Giulia
MG
Bacalini
Massimo
M
De Felici
Paola
P
Caiafa
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; D011064:Poly Adenosine Diphosphate Ribose; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases