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

Item Type:Article
Title:Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator
Creators Name:Allou, L. and Balzano, S. and Magg, A. and Quinodoz, M. and Royer-Bertrand, B. and Schöpflin, R. and Chan, W.L. and Speck-Martins, C.E. and Carvalho, D.R. and Farage, L. and Lourenço, C.M. and Albuquerque, R. and Rajagopal, S. and Nampoothiri, S. and Campos-Xavier, B. and Chiesa, C. and Niel-Bütschi, F. and Wittler, L. and Timmermann, B. and Spielmann, M. and Robson, M.I. and Ringel, A. and Heinrich, V. and Cova, G. and Andrey, G. and Prada-Medina, C.A. and Pescini-Gobert, R. and Unger, S. and Bonafé, L. and Grote, P. and Rivolta, C. and Mundlos, S. and Superti-Furga, A.
Abstract:Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks, 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.
Keywords:Animal Disease Models, Cell Line, Chromatin, Congenital Limb Deformities, Extremities, Genetic Transcription, Homeodomain Proteins, Long Noncoding RNA, Sequence Deletion, Transcriptional Activation, Transgenic Mice, Animals, Mice
Publisher:Nature Publishing Group
Page Range:93-98
Date:1 April 2021
Official Publication:https://doi.org/10.1038/s41586-021-03208-9
PubMed:View item in PubMed

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