Allele-specific histone modifications regulate expression of the Dlk1-Gtl2 imprinted domain.
Dlk1 and Gtl2 are reciprocally expressed imprinted genes located on mouse chromosome 12. The Dlk1-Gtl2 locus carries three differentially methylated regions (DMRs), which are methylated only on the paternal allele. Of these, the intergenic (IG) DMR, located 12 kb upstream of Gtl2, is required for proper imprinting of linked genes on the maternal chromosome, while the Gtl2 DMR, located across the promoter of the Gtl2 gene, is implicated in imprinting on both parental chromosomes. In addition to DNA methylation, modification of histone proteins is also an important regulator of imprinted gene expression. Chromatin immunoprecipitation was therefore used to examine the pattern of histone modifications across the IG and Gtl2 DMRs. The data show maternal-specific histone acetylation at the Gtl2 DMR, but not at the IG DMR. In contrast, only low levels of histone methylation were observed throughout the region, and there was no difference between the two parental alleles. An existing mouse line carrying a deletion/insertion upstream of Gtl2 is unable to imprint the Dlk1-Gtl2 locus properly and demonstrates loss of allele-specific methylation at the Gtl2 DMR. Further analysis of these animals now shows that the loss of allele-specific methylation is accompanied by increased paternal histone acetylation at the Gtl2 DMR, with the activated paternal allele adopting a maternal acetylation pattern. These data indicate that interactions between DNA methylation and histone acetylation are involved in regulating the imprinting of the Dlk1-Gtl2 locus.
Carr
Michael S
MS
Department of Biological Sciences, The University of Illinois at Chicago, 900 S. Ashland Avenue, MC 567, Chicago, IL 60607, USA.
Yevtodiyenko
Aleksey
A
Schmidt
Claudia L
CL
Schmidt
Jennifer V
JV
D000107:Acetylation; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D000076246:CCCTC-Binding Factor; D002135:Calcium-Binding Proteins; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005260:Female; D018392:Genomic Imprinting; D006657:Histones / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007438:Introns; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016297:Mutagenesis, Site-Directed; D011247:Pregnancy; D011485:Protein Binding; D011506:Proteins / Q000235:genetics*; D062085:RNA, Long Noncoding; D012097:Repressor Proteins / Q000378:metabolism; D050986:YY1 Transcription Factor / Q000378:metabolism
D000076246:CCCTC-Binding Factor; D002135:Calcium-Binding Proteins; C000619698:Ctcf protein, mouse; D004268:DNA-Binding Proteins; C512925:Dlk1 protein, mouse; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; C422882:MEG3 non-coding RNA, mouse; D011506:Proteins; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse; D004247:DNA