title: Imprinted chromatin around DIRAS3 regulates alternative splicing of GNG12-AS1, a long noncoding RNA.
abstract: Imprinted gene clusters are regulated by long noncoding RNAs (lncRNAs), CCCTC binding factor (CTCF)-mediated boundaries, and DNA methylation. DIRAS3 (also known as ARH1 or NOEY1) is an imprinted gene encoding a protein belonging to the RAS superfamily of GTPases and is located within an intron of a lncRNA called GNG12-AS1. In this study, we investigated whether GNG12-AS1 is imprinted and coregulated with DIRAS3. We report that GNG12-AS1 is coexpressed with DIRAS3 in several tissues and coordinately downregulated with DIRAS3 in breast cancers. GNG12-AS1 has several splice variants, all of which initiate from a single transcription start site. In placenta tissue and normal cell lines, GNG12-AS1 is biallelically expressed but some isoforms are allele-specifically spliced. Cohesin plays a role in allele-specific splicing of GNG12-AS1. In breast cancer cell lines with loss of DIRAS3 imprinting, DIRAS3 and GNG12-AS1 are silenced in cis and the remaining GNG12-AS1 transcripts are predominantly monoallelic. The GNG12-AS1 locus, which includes DIRAS3, provides an example of imprinted cotranscriptional splicing and a potential model system for studying the long-range effects of CTCF-cohesin binding on splicing and transcriptional interference.
authors.affiliation: Cancer Research UK, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Malwina
authors.initials: M
authors.lastname: Niemczyk
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ito
authors.forename: Joanna
authors.initials: J
authors.lastname: Huddleston
authors.forename: Anna
authors.initials: A
authors.lastname: Git
authors.forename: Sayeda
authors.initials: S
authors.lastname: Abu-Amero
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: Gudrun E
authors.initials: GE
authors.lastname: Moore
authors.forename: Lovorka
authors.initials: L
authors.lastname: Stojic
authors.forename: Adele
authors.initials: A
authors.lastname: Murrell
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D005786:Gene Expression Regulation; D018392:Genomic Imprinting; D006801:Humans; D007438:Introns; D010920:Placenta / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D062085:RNA, Long Noncoding; D020741:rho GTP-Binding Proteins; D000097722:Cohesins; C117386:DIRAS3 protein, human