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  Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator

Allou, L., Balzano, S., Magg, A., Quinodoz, M., Royer-Bertrand, B., Schöpflin, R., et al. (2021). Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator. Nature. doi:10.1038/s41586-021-03208-9.

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Allou, Lila1, Author              
Balzano, Sara, Author
Magg, Andreas1, Author              
Quinodoz, Mathieu , Author
Royer-Bertrand, Beryl , Author
Schöpflin, Robert1, Author              
Chan, Wing-Lee , Author
Speck-Martins, Carlos E. , Author
Rocha Carvalho, Daniel , Author
Farage, Luciano, Author
Marques Lourenço, Charles , Author
Albuquerque, Regina , Author
Rajagopal, Srilakshmi , Author
Nampoothiri, Sheela , Author
Campos-Xavier, Belinda , Author
Chiesa, Carole , Author
Niel-Bütschi, Florence , Author
Wittler, Lars2, Author              
Timmermann, Bernd3, Author              
Spielmann, Malte4, Author              
Robson, Michael1, Author              Ringel, Alessa1, Author              Heinrich, Verena5, Author              Cova, Giulia1, Author              Andrey , Guillaume 1, AuthorPrada-Medina, Cesar A. 1, AuthorPescini-Gobert, Rosanna, AuthorUnger, Sheila , AuthorBonafé, Luisa , AuthorGrote, Phillip , AuthorRivolta, Carlo , AuthorMundlos, Stefan1, Author              Superti-Furga, Andrea , Author more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
3Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
4Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014183              
5Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              

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 Abstract: Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks1, but the exact nature and extent of their involvement in human Mendelian disease is largely unknown. Here we show that genetic ablation of a lncRNA locus on human chromosome 2 causes a severe congenital limb malformation. We identified homozygous 27-63-kilobase deletions located 300 kilobases upstream of the engrailed-1 gene (EN1) in patients with a complex limb malformation featuring mesomelic shortening, syndactyly and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of En1 expression in the limb and a double dorsal-limb phenotype that recapitulates the human disease phenotype. Genome-wide transcriptome analysis in the developing mouse limb revealed a four-exon-long non-coding transcript within the deleted region, which we named Maenli. Functional dissection of the Maenli locus showed that its transcriptional activity is required for limb-specific En1 activation in cis, thereby fine-tuning the gene-regulatory networks controlling dorso-ventral polarity in the developing limb bud. Its loss results in the En1-related dorsal ventral limb phenotype, a subset of the full En1-associated phenotype. Our findings demonstrate that mutations involving lncRNA loci can result in human Mendelian disease.

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Language(s): eng - English
 Dates: 2021-01-072021-02-10
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/s41586-021-03208-9
PMID: 33568816
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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: - Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238