title: Imprinting at the PLAGL1 domain is contained within a 70-kb CTCF/cohesin-mediated non-allelic chromatin loop.
abstract: Paternal duplications of chromosome 6q24, a region that contains the imprinted PLAGL1 and HYMAI transcripts, are associated with transient neonatal diabetes mellitus. A common feature of imprinted genes is that they tend to cluster together, presumably as a result of sharing common cis-acting regulatory elements. To determine the extent of this imprinted cluster in human and mouse, we have undertaken a systematic analysis of allelic expression and DNA methylation of the genes mapping within an ∼1.4-Mb region flanking PLAGL1/Plagl1. We confirm that all nine neighbouring genes are biallelically expressed in both species. In human we identify two novel paternally expressed PLAGL1 coding transcripts that originate from unique promoter regions. Chromatin immunoprecipitation for CTCF and the cohesin subunits RAD21 and SMC3 reveals evolutionarily conserved binding sites within unmethylated regions ∼5 kb downstream of the PLAGL1 differentially methylated region and within the PLAGL1 3' untranslated region (UTR). Higher-order chromatin looping occurs between these regions in both expressing and non-expressing tissues, forming a non-allelic chromatin loop around the PLAGL1/Plagl1 gene. In placenta and brain tissues, we identify an additional interaction between the PLAGL1 P3/P4 promoters and the unmethylated element downstream of the PLAGL1 differentially methylated region that we propose facilitates imprinted expression of these alternative isoforms.
authors.affiliation: Servicio de Neonatología, Hospital Sant Joan de Déu (HSJD), Fundació Sant Joan de Déu, 08950 Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Iglesias-Platas
authors.forename: Franck
authors.initials: F
authors.lastname: Court
authors.forename: Cristina
authors.initials: C
authors.lastname: Camprubi
authors.forename: Angela
authors.initials: A
authors.lastname: Sparago
authors.forename: Amy
authors.initials: A
authors.lastname: Guillaumet-Adkins
authors.forename: Alex
authors.initials: A
authors.lastname: Martin-Trujillo
authors.forename: Andrea
authors.initials: A
authors.lastname: Riccio
authors.forename: Gudrun E
authors.initials: GE
authors.lastname: Moore
authors.forename: David
authors.initials: D
authors.lastname: Monk
mesh_terms: D000483:Alleles; D000818:Animals; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D002896:Chromosomes, Human, Pair 6; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016147:Genes, Tumor Suppressor; D018392:Genomic Imprinting; D005838:Genotype; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D000097722:Cohesins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D000097722:Cohesins; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; C509782:HYMAI, RNA; C104382:PLAG1 protein, human; C543104:PHACTR2 protein, human; C498423:Plagl1 protein, mouse