CTCF-dependent chromatin bias constitutes transient epigenetic memory of the mother at the H19-Igf2 imprinting control region in prospermatogonia.
Genomic imprints-parental allele-specific DNA methylation marks at the differentially methylated regions (DMRs) of imprinted genes-are erased and reestablished in germ cells according to the individual's sex. Imprint establishment at paternally methylated germ line DMRs occurs in fetal male germ cells. In prospermatogonia, the two unmethylated alleles exhibit different rates of de novo methylation at the H19/Igf2 imprinting control region (ICR) depending on parental origin. We investigated the nature of this epigenetic memory using bisulfite sequencing and allele-specific ChIP-SNuPE assays. We found that the chromatin composition in fetal germ cells was biased at the ICR between the two alleles with the maternally inherited allele exhibiting more H3K4me3 and less H3K9me3 than the paternally inherited allele. We determined genetically that the chromatin bias, and also the delayed methylation establishment in the maternal allele, depended on functional CTCF insulator binding sites in the ICR. Our data suggest that, in primordial germ cells, maternally inherited allele-specific CTCF binding sets up allele-specific chromatin differences at the ICR. The erasure of these allele-specific chromatin marks is not complete before the process of de novo methylation imprint establishment begins. CTCF-dependent allele-specific chromatin composition imposes a maternal allele-specific delay on de novo methylation imprint establishment at the H19/Igf2 ICR in prospermatogonia.
Department of Molecular and Cellular Biology, Beckman Research Institute, Duarte, CA, USA.
Dong-Hoon
DH
Lee
Purnima
P
Singh
Shirley Y
SY
Tsai
Nathan
N
Oates
Alexander
A
Spalla
Claudio
C
Spalla
Lucy
L
Brown
Guillermo
G
Rivas
Garrett
G
Larson
Tibor A
TA
Rauch
Gerd P
GP
Pfeifer
Piroska E
PE
Szabó
D000483:Alleles; D000818:Animals; D000076246:CCCTC-Binding Factor; D002843:Chromatin / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D018392:Genomic Imprinting; D006657:Histones / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D013093:Spermatogonia / Q000166:cytology / Q000378:metabolism*; D013447:Sulfites
D000076246:CCCTC-Binding Factor; D002843:Chromatin; C000619698:Ctcf protein, mouse; C094335:H19 long non-coding RNA; D006657:Histones; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012097:Repressor Proteins; D013447:Sulfites; D007335:Insulin-Like Growth Factor II; D008239:Lysine; C042345:hydrogen sulfite