Imprint control element-mediated secondary methylation imprints at the Igf2/H19 locus.
Understanding the molecular basis of monoallelic expression as observed at imprinted loci is helpful in understanding the mechanisms underlying epigenetic regulation. Genomic imprinting begins during gametogenesis with the establishment of epigenetic marks on the chromosomes such that paternal and maternal chromosomes are rendered distinct. During embryonic development, the primary imprint can lead to generation of secondary epigenetic modifications (secondary imprints) of the chromosomes. Eventually, either the primary imprints or the secondary imprints interfere with transcription, leading to parent-of-origin-dependent silencing of one of the two alleles. Here we investigated several aspects pertaining to the generation and functional necessity of secondary methylation imprints at the Igf2/H19 locus. At the H19 locus, these secondary imprints are, in fact, the signals mediating paternal chromosome-specific silencing of that gene. We first demonstrated that the H19 secondary methylation imprints are entirely stable through multiple cell divisions, even in the absence of the primary imprint. Second, we generated mouse mutations to determine which DNA sequences are important in mediating establishment and maintenance of the silent state of the paternal H19 allele. Finally, we analyzed the dependence of the methylation of Igf2DMR1 region on the primary methylation imprint about 90 kilobases away.
Srivastava
Madhulika
M
Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892,USA. madhus@nii.res.in
Frolova
Ella
E
Rottinghaus
Brian
B
Boe
Steven P
SP
Grinberg
Alexander
A
Lee
Eric
E
Love
Paul E
PE
Pfeifer
Karl
K
D000818:Animals; D001483:Base Sequence; D018801:CD2 Antigens / Q000235:genetics; D002874:Chromosome Mapping; D019175:DNA Methylation; D017931:DNA Primers; D005314:Embryonic and Fetal Development; D005091:Exons; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D015183:Restriction Mapping; D013601:T-Lymphocytes / Q000276:immunology
D018801:CD2 Antigens; D017931:DNA Primers; C094335:H19 long non-coding RNA; C420116:Ihit1 protein, mouse; D011506:Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II