title: Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder.
abstract: An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Szafranski
authors.forename: Avinash V
authors.initials: AV
authors.lastname: Dharmadhikari
authors.forename: Erwin
authors.initials: E
authors.lastname: Brosens
authors.forename: Priyatansh
authors.initials: P
authors.lastname: Gurha
authors.forename: Katarzyna E
authors.initials: KE
authors.lastname: Kolodziejska
authors.forename: Ou
authors.initials: O
authors.lastname: Zhishuo
authors.forename: Piotr
authors.initials: P
authors.lastname: Dittwald
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Majewski
authors.forename: K Naga
authors.initials: KN
authors.lastname: Mohan
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.forename: Richard E
authors.initials: RE
authors.lastname: Person
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
authors.forename: Jason
authors.initials: J
authors.lastname: Pinner
authors.forename: Maya
authors.initials: M
authors.lastname: Chopra
authors.forename: Girvan
authors.initials: G
authors.lastname: Malcolm
authors.forename: Gregory
authors.initials: G
authors.lastname: Peters
authors.forename: Susan
authors.initials: S
authors.lastname: Arbuckle
authors.forename: Sixto F
authors.initials: SF
authors.lastname: Guiang
authors.forename: Virginia A
authors.initials: VA
authors.lastname: Hustead
authors.forename: Jose
authors.initials: J
authors.lastname: Jessurun
authors.forename: Russel
authors.initials: R
authors.lastname: Hirsch
authors.forename: David P
authors.initials: DP
authors.lastname: Witte
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maystadt
authors.forename: Neil
authors.initials: N
authors.lastname: Sebire
authors.forename: Richard
authors.initials: R
authors.lastname: Fisher
authors.forename: Claire
authors.initials: C
authors.lastname: Langston
authors.forename: Partha
authors.initials: P
authors.lastname: Sen
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
mesh_terms: D002843:Chromatin / Q000378:metabolism; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D018899:CpG Islands; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D017809:Fatal Outcome; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D018392:Genomic Imprinting; D057809:HEK293 Cells; D006801:Humans; D007231:Infant, Newborn; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010547:Persistent Fetal Circulation Syndrome / Q000175:diagnosis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D014158:Transcription, Genetic; D000075746:Zinc Finger Protein Gli2
chemical_list: D002843:Chromatin; C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors; C082593:GLI2 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D000075746:Zinc Finger Protein Gli2