Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder

被引:114
作者
Szafranski, Przemyslaw [1 ]
Dharmadhikari, Avinash V. [1 ,2 ]
Brosens, Erwin [3 ,4 ]
Gurha, Priyatansh [1 ,5 ,6 ]
Kolodziejska, Katarzyna E. [1 ]
Ou Zhishuo [1 ]
Dittwald, Piotr [1 ,7 ,8 ]
Majewski, Tadeusz [9 ]
Mohan, K. Naga [1 ,10 ]
Chen, Bo [1 ]
Person, Richard E. [1 ]
Tibboel, Dick [4 ]
de Klein, Annelies [3 ]
Pinner, Jason [11 ]
Chopra, Maya [11 ]
Malcolm, Girvan [12 ]
Peters, Gregory [13 ]
Arbuckle, Susan [14 ]
Guiang, Sixto F., III [15 ]
Hustead, Virginia A. [16 ]
Jessurun, Jose [17 ]
Hirsch, Russel [18 ]
Witte, David P. [18 ]
Maystadt, Isabelle [19 ]
Sebire, Neil [20 ,21 ]
Fisher, Richard [22 ]
Langston, Claire [23 ,24 ]
Sen, Partha [25 ]
Stankiewicz, Pawel [1 ,2 ]
机构
[1] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[2] Baylor Coll Med, Program Translat Biol & Mol Med, Houston, TX 77030 USA
[3] Erasmus MC Sophia, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands
[4] Erasmus MC Sophia, NL-3015 GJ Rotterdam, Netherlands
[5] Univ Texas Hlth Sci Ctr, Brown Fdn Inst Mol Med, Ctr Cardiovasc Genet, Houston, TX 77030 USA
[6] St Lukes Episcopal Hosp, Texas Heart Inst, Houston, TX 77030 USA
[7] Univ Warsaw, Inst Informat, PL-02097 Warsaw, Poland
[8] Univ Warsaw, Coll Interfac Individual Studies Math & Nat Sci, PL-02089 Warsaw, Poland
[9] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA
[10] Birla Inst Technol & Sci Pilani, Dept Biol Sci, Hyderabad 500078, Andhra Pradesh, India
[11] Royal Prince Alfred Hosp, Dept Mol & Clin Genet, Sydney, NSW 2050, Australia
[12] Royal Prince Alfred Hosp, Sydney, NSW 2006, Australia
[13] Childrens Hosp Westmead, Dept Cytogenet, Westmead, NSW 2145, Australia
[14] Childrens Hosp Westmead, Dept Histopathol, Westmead, NSW 2145, Australia
[15] Univ Minnesota, Med Ctr, Dept Pediat Neonatol, Minneapolis, MN 55454 USA
[16] Minnesota Neonatal Phys, Minneapolis, MN 55404 USA
[17] Univ Minnesota, Med Ctr, Dept Med, Lab Med & Pathol, Minneapolis, MN 55454 USA
[18] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA
[19] Inst Pathol & Genet, B-6041 Gosselies, Belgium
[20] Great Ormond St Hosp Sick Children, Dept Paediat Histopathol, London WC1N 3JH, England
[21] UCL Inst Child Hlth, London WC1N 3JH, England
[22] James Cook Univ Hosp, Middlesbrough TS4 3BW, England
[23] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA
[24] Texas Childrens Hosp, Houston, TX 77030 USA
[25] Baylor Coll Med, Dept Pediat Neonatol, Houston, TX 77030 USA
关键词
ALVEOLAR-CAPILLARY DYSPLASIA; TRANSCRIPTION-FACTOR; RNAS; GENOME; FOXF1; MECHANISMS; EXPRESSION; ELEMENTS; BINDING; IDENTIFICATION;
D O I
10.1101/gr.141887.112
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:23 / 33
页数:11
相关论文
共 55 条
  • [1] Genomic imprinting: employing and avoiding epigenetic processes
    Bartolomei, Marisa S.
    [J]. GENES & DEVELOPMENT, 2009, 23 (18) : 2124 - 2133
  • [2] Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
    Birney, Ewan
    Stamatoyannopoulos, John A.
    Dutta, Anindya
    Guigo, Roderic
    Gingeras, Thomas R.
    Margulies, Elliott H.
    Weng, Zhiping
    Snyder, Michael
    Dermitzakis, Emmanouil T.
    Stamatoyannopoulos, John A.
    Thurman, Robert E.
    Kuehn, Michael S.
    Taylor, Christopher M.
    Neph, Shane
    Koch, Christoph M.
    Asthana, Saurabh
    Malhotra, Ankit
    Adzhubei, Ivan
    Greenbaum, Jason A.
    Andrews, Robert M.
    Flicek, Paul
    Boyle, Patrick J.
    Cao, Hua
    Carter, Nigel P.
    Clelland, Gayle K.
    Davis, Sean
    Day, Nathan
    Dhami, Pawandeep
    Dillon, Shane C.
    Dorschner, Michael O.
    Fiegler, Heike
    Giresi, Paul G.
    Goldy, Jeff
    Hawrylycz, Michael
    Haydock, Andrew
    Humbert, Richard
    James, Keith D.
    Johnson, Brett E.
    Johnson, Ericka M.
    Frum, Tristan T.
    Rosenzweig, Elizabeth R.
    Karnani, Neerja
    Lee, Kirsten
    Lefebvre, Gregory C.
    Navas, Patrick A.
    Neri, Fidencio
    Parker, Stephen C. J.
    Sabo, Peter J.
    Sandstrom, Richard
    Shafer, Anthony
    [J]. NATURE, 2007, 447 (7146) : 799 - 816
  • [3] Alveolar Capillary Dysplasia
    Bishop, Naomi B.
    Stankiewicz, Pawel
    Steinhorn, Robin H.
    [J]. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2011, 184 (02) : 172 - 179
  • [4] Mesenchymal Stromal Cells from Neonatal Tracheal Aspirates Demonstrate a Pattern of Lung-Specific Gene Expression
    Bozyk, Paul D.
    Popova, Antonia P.
    Bentley, John Kelley
    Goldsmith, Adam M.
    Linn, Marisa J.
    Weiss, Daniel J.
    Hershenson, Marc B.
    [J]. STEM CELLS AND DEVELOPMENT, 2011, 20 (11) : 1995 - 2007
  • [5] Structural characterization of the mouse Foxf1a gene
    Chang, VWH
    Ho, YS
    [J]. GENE, 2001, 267 (02) : 201 - 211
  • [6] Disease-Causing 7.4 kb Cis-Regulatory Deletion Disrupting Conserved Non-Coding Sequences and Their Interaction with the FOXL2 Promotor: Implications for Mutation Screening
    D'haene, Barbara
    Attanasio, Catia
    Beysen, Diane
    Dostie, Josee
    Lemire, Edmond
    Bouchard, Philippe
    Field, Michael
    Jones, Kristie
    Lorenz, Birgit
    Menten, Bjorn
    Buysse, Karen
    Pattyn, Filip
    Friedli, Marc
    Ucla, Catherine
    Rossier, Colette
    Wyss, Carine
    Speleman, Frank
    De Paepe, Anne
    Dekker, Job
    Antonarakis, Stylianos E.
    De Baere, Elfride
    [J]. PLOS GENETICS, 2009, 5 (06):
  • [7] Small Deletion Variants Have Stable Breakpoints Commonly Associated with Alu Elements
    de Smith, Adam J.
    Walters, Robin G.
    Coin, Lachlan J. M.
    Steinfeld, Israel
    Yakhini, Zohar
    Sladek, Rob
    Froguel, Philippe
    Blakemore, Alexandra I. F.
    [J]. PLOS ONE, 2008, 3 (08):
  • [8] Mapping networks of physical interactions between genomic elements using 5C technology
    Dostie, Josee
    Dekker, Job
    [J]. NATURE PROTOCOLS, 2007, 2 (04) : 988 - 1002
  • [9] 14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype
    Ellaway, Carolyn J.
    Ho, Gladys
    Bettella, Elisa
    Knapman, Alisa
    Collins, Felicity
    Hackett, Anna
    McKenzie, Fiona
    Darmanian, Artur
    Peters, Gregory B.
    Fagan, Kerry
    Christodoulou, John
    [J]. EUROPEAN JOURNAL OF HUMAN GENETICS, 2013, 21 (05) : 522 - 527
  • [10] Alveolar capillary dysplasia: a six-year single center experience
    Eulmesekian, P
    Cutz, E
    Parvez, B
    Bohn, D
    Adatia, I
    [J]. JOURNAL OF PERINATAL MEDICINE, 2005, 33 (04) : 347 - 352