Regulation of imprinting in clusters: noncoding RNAs versus insulators.
Genomic imprinting is an epigenetic mechanism of transcriptional regulation through which expression of a subset of mammalian genes is restricted to one parental allele. An intriguing characteristic of imprinted genes is that they often cluster in megabase-sized chromosomal domains, indicating that domain-specific mechanisms regulate imprinting. Detailed study of the known imprinted domains has revealed a number of common characteristics. First, all clusters have an imprinting control region (ICR) that is typically 1-5 kb in size and differentially methylated, and that regulates imprinting across the entire domain. Second, the clusters have at least one noncoding RNA (ncRNA) that is usually expressed from the maternal allele and multiple paternally expressed protein-coding genes. Finally, the clusters are likely regulated by one of two mechanisms, transcription of a long ncRNA that silences expression of protein-coding genes bidirectionally in cis and blocking of shared enhancer elements by CCCTC binding factor (CTCF) binding insulators. More recent experiments may even suggest that both mechanisms operate at some clusters. In this chapter, we will describe what is known about imprinting at five well-studied imprinted loci and highlight some of the critical experiments that are required before a full understanding of imprinting mechanisms is achieved.
Wan
Le-Ben
LB
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Bartolomei
Marisa S
MS
D000818:Animals; D002135:Calcium-Binding Proteins; D020868:Gene Silencing / Q000502:physiology; D018392:Genomic Imprinting / Q000235:genetics* / Q000502:physiology; D006801:Humans; D038101:Insulator Elements / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008954:Models, Biological; D005810:Multigene Family / Q000235:genetics* / Q000502:physiology; D011506:Proteins / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics / Q000502:physiology*; D020666:ras-GRF1 / Q000235:genetics
D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; C094335:H19 long non-coding RNA; D036341:Intercellular Signaling Peptides and Proteins; D051657:KCNQ1 Potassium Channel; C498907:MEG3 non-coding RNA, human; D008565:Membrane Proteins; D011506:Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D020666:ras-GRF1; D007335:Insulin-Like Growth Factor II