Two distinct mechanisms of silencing by the KvDMR1 imprinting control region.
Imprinting control regions (ICRs) are known to repress genes by utilizing one of two mechanisms, CTCF-mediated insulation or the transcription of non-coding RNAs (ncRNAs). The KvDMR1 ICR contains both the promoter for the Kcnq1ot1 ncRNA and two CTCF-binding sites located within sequences exhibiting repressive activity in enhancer-blocking assays. Deletion of KvDMR1 results in ubiquitous biallelic expression of eight maternal-specific genes in distal chromosome 7. Here we report that while truncation of the Kcnq1ot1 transcript results in the loss of imprinted expression of these genes in the placenta, it does not affect imprinted expression of Cdkn1c in a subset of embryonic tissues despite universal loss of paternal-specific methylation at Cdkn1c. Consistent with tissue-specific loss of imprinted expression, growth deficiency of these mutant mice was less severe than that observed previously in mice with deletion of KvDMR1. This study demonstrates that the KvDMR1 locus can silence Cdkn1c by a mechanism independent of Kcnq1ot1 transcription, perhaps by CTCF-associated repression, making it the first example of an ICR capable of silencing the same gene by two distinct mechanisms.
Shin
Jong-Yeon
JY
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Fitzpatrick
Galina V
GV
Higgins
Michael J
MJ
D000818:Animals; D000076246:CCCTC-Binding Factor; D002478:Cells, Cultured; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000037:antagonists & inhibitors / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D005260:Female; D020868:Gene Silencing / Q000502:physiology*; D018392:Genomic Imprinting / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024642:Potassium Channels, Voltage-Gated / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology
D000076246:CCCTC-Binding Factor; C493964:CDKN1C protein, human; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004268:DNA-Binding Proteins; C485621:KCNQ1OT1 long non-coding RNA, human; D008565:Membrane Proteins; D024642:Potassium Channels, Voltage-Gated; D012097:Repressor Proteins