title: Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1.
abstract: A long noncoding RNA, Kcnq1ot1, regulates the expression of both ubiquitously and tissue-specific imprinted genes within the Kcnq1 domain. However, the functional sequences of the Kcnq1ot1 RNA that mediate lineage-specific imprinting are unknown. Here, we have generated a knockout mouse with a deletion encompassing an 890-bp silencing domain (Delta890) downstream of the Kcnq1ot1 promoter. Maternal transmission of the Delta890 allele has no effect on imprinting, whereas paternal inheritance of the deletion leads to selective relaxation of the imprinting of ubiquitously imprinted genes to a variable extent in a tissue-specific manner. Interestingly, the deletion affects DNA methylation at somatically acquired differentially methylated regions (DMRs), but does not affect the histone modifications of the ubiquitously imprinted genes. Importantly, we found that Kcnq1ot1 recruits Dnmt1 to somatic DMRs by interacting with Dnmt1, and that this interaction was significantly reduced in the Delta890 mice. Thus, the ubiquitous and placental-specific imprinting of genes within the Kcnq1 domain might be mediated by distinct mechanisms, and Kcnq1ot1 RNA might mediate the silencing of ubiquitously imprinted genes by maintaining allele-specific methylation through its interactions with Dnmt1.
authors.affiliation: Department of Genetics and Pathology, Dag Hammarskjölds Väg 20, 75185 Rudbeck Laboratory, Uppsala University, Uppsala 75185, Sweden.
authors.forename: Faizaan
authors.initials: F
authors.lastname: Mohammad
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Mondal
authors.forename: Natalia
authors.initials: N
authors.lastname: Guseva
authors.forename: Gaurav Kumar
authors.initials: GK
authors.lastname: Pandey
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Kanduri
mesh_terms: D000483:Alleles; D000818:Animals; D002843:Chromatin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D018392:Genomic Imprinting; D051379:Mice; D009154:Mutation; D017434:Protein Structure, Tertiary; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; C449939:KCNQ1OT1 RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse