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Series GSE137333 Query DataSets for GSE137333
Status Public on Oct 25, 2020
Title Loss of Maenli lncRNA expression causes engrailed-1 dependent congenital limb malformations [Capture Hi-C]
Organism Mus musculus
Experiment type Other
Summary Long non-coding RNAs (lncRNAs) can be important components in gene regulatory networks1, but we are only beginning to understand the nature and extent of their involvement in human Mendelian disease. Here we show that deletions of an unannotated lncRNA locus on human chromosome 2 cause a severe congenital limb malformation. Using exome sequencing and array CGH, we identified homozygous 27-63 kb deletions located 300 kb upstream of the engrailed-1 (EN1) gene 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 limb-specific En1 expression and a double dorsal limb phenotype, recapitulating the human malformation. Genome-wide analysis in the developing mouse limb revealed the presence of a 4-exon long non-coding transcript within the deleted region, which we named Maenli (for Master activator of En1 in the limb). Functional dissection of the Maenli locus showed that limb-specific En1 expression depends on transcription of Maenli and its loss resulted in the double dorsal limb phenotype. Concomitant monoallelic inactivation of En1 and Maenli in double heterozygous mice did not rescue the limb phenotype, indicating that En1 activation in the limb requires the cis-acting regulatory element Maenli. Moreover, our results strongly suggest that En1 activation is dependent on Maenli transcription, but not on the Maenli RNA itself. Thus, Maenli expression in the limb acts in cis to promote En1 transcriptional activation; its loss results in congenital malformation of the limbs, a subset of the full En1 associated phenotype. Together, our findings provide evidence that mutations involving lncRNAs loci can result in human Mendelian disease.
Overall design We used exome sequencing and array CGH to analyze patients' samples, CRISPR experiments to investigate the effect of the potential pathogenic variants, genome wide analysis to identify a new lncRNA locus, and functional studies to characterize the effect of the knockout lncRNA locus.
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Contributor(s) Allou L
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Submission date Sep 12, 2019
Last update date Feb 09, 2021
Contact name Lila Allou
Organization name Max Planck Institute For Molecular Genetics
Department FG Development and Disease
Lab FG Mundlos
Street address 63-73 Ihnestrasse
City Berlin
ZIP/Postal code 14195
Country Germany
Platforms (1)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (11)
GSM4498650 mpimg_L12976-1_CD1FLE9-5-cHiC
GSM4498651 mpimg_L12977-1_CD1FLE9-5-cHiC
GSM4498652 mpimg_L12978-1_CD1FLE9-5-cHiC
This SubSeries is part of SuperSeries:
GSE137335 Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator
BioProject PRJNA565204
SRA SRP221478

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Supplementary file Size Download File type/resource
GSE137333_mpimg_L12976_L12977_L12978_CD1FLE9-5_Rep1_Rep2_Rep3_merged.hicup.MAPQ30.KR_10kb-cHiC.WashU.txt.gz 840.0 Kb (ftp)(http) TXT
GSE137333_mpimg_L12976_L12977_L12978_CD1FLE9-5_Rep1_Rep2_Rep3_merged.hicup.MAPQ30.Raw_10kb-cHiC.WashU.txt.gz 454.5 Kb (ftp)(http) TXT
GSE137333_mpimg_L19076_L19077_L19078_E9-5-FB-Rep1_Rep2_Rep3_merged.hicup.MAPQ30.KR_10kb-cHiC.WashU.txt.gz 841.5 Kb (ftp)(http) TXT
GSE137333_mpimg_L19076_L19077_L19078_E9-5-FB-Rep1_Rep2_Rep3_merged.hicup.MAPQ30.Raw_10kb-cHiC.WashU.txt.gz 454.3 Kb (ftp)(http) TXT
GSE137333_mpimg_L19079_L19080_L19081_E9-5-MHB-Rep1_Rep2_Rep3_merged.hicup.MAPQ30.KR_10kb-cHiC.WashU.txt.gz 838.8 Kb (ftp)(http) TXT
GSE137333_mpimg_L19079_L19080_L19081_E9-5-MHB-Rep1_Rep2_Rep3_merged.hicup.MAPQ30.Raw_10kb-cHiC.WashU.txt.gz 453.5 Kb (ftp)(http) TXT
GSE137333_mpimg_L19377_L19378_E9-5FL3xpA_Rep2_Rep3_merged.hicup.MAPQ30.KR_10kb-cHiC.WashU.txt.gz 838.6 Kb (ftp)(http) TXT
GSE137333_mpimg_L19377_L19378_E9-5FL3xpA_Rep2_Rep3_merged.hicup.MAPQ30.Raw_10kb-cHiC.WashU.txt.gz 448.8 Kb (ftp)(http) TXT
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