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Series GSE165491 Query DataSets for GSE165491
Status Public on Jul 20, 2021
Title Mesomelic Dysplasias Associated With The HOXD Locus Are Caused By Regulatory Reallocations [cHi-C]
Organism Mus musculus
Experiment type Other
Summary Some human families display severe shortening and bending of the radius and ulna, a condition referred to as mesomelic dysplasia. Many of these families contain chromosomal rearrangements at 2q31, where the human HOXD locus maps. In mice, the dominant X-ray-induced Ulnaless inversion of the HoxD gene cluster produces a similar phenotype suggesting that the same pathological mechanism is at work in humans and mice. A tentative hypothesis was proposed where the various alterations to the genomic structure of HOXD could translocate Hoxd13 near to proximal limb enhancers, leading to its deleterious gain-of-expression in the embryonic forelimb. We evaluated this hypothesis by engineering a ca. 1Mb large inversion including the HoxD gene cluster, in order to position Hoxd13 within a chromatin domain rich in proximal limb enhancers. We show that these enhancers contact and activate Hoxd13 in proximal cells, concomitant to the formation of a mesomelic dysplasia phenotype. A secondary mutation in the coding frame of the HOXD13 protein in-cis with the inversion completely rescued the limb alterations, demonstrating that ectopic HOXD13 is indeed the unique cause of this bone anomaly. Single cell expression analysis and evaluation of HOXD13 binding sites in cells from this ectopic expression domain suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
Overall design wild type and mutant (inv2) tissue samples were collected from E12.5 mouse embryos. Proximal limb domain, and distal limb domains were collected and processed as described in Buenrostro 2013.
Contributor(s) Bolt CC, Mascrez B, Lopez-Delisle L, Duboule D
Citation(s) 34408147
Submission date Jan 25, 2021
Last update date Jan 20, 2022
Contact name Lucille Lopez-Delisle
Organization name EPFL
Street address Station 19
City Lausanne
ZIP/Postal code 1015
Country Switzerland
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (6)
GSM5034635 E12.5 wild type proximal forelimb capture Hi-C
GSM5034636 E12.5 wild type distal forelimb capture Hi-C
GSM5034637 E12.5 wild type forebrain capture Hi-C
This SubSeries is part of SuperSeries:
GSE165495 Mesomelic Dysplasias Associated With The HOXD Locus Are Caused By Regulatory Reallocations
BioProject PRJNA694680
SRA SRP303199

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE165491_RAW.tar 2.9 Gb (http)(custom) TAR (of COOL, TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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