Cumulative in-cis mutagenesis in vivo reveals various functions for CTCF sites at the mouse Hoxd cluster [cHi-C]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE181386 | GEO | 2021/10/05
REPOSITORIES: GEO
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Project description:RNA-seq analysis of the effect of CRISPR/Cas9-induced CTCF binding sites deletions on gene expression. We studied E12.5 distal or proximal forelimbs of wildtype and mutant alleles.
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Project description:During limb development, Hoxd genes are transcribed in two waves: Early on, when the arm and forearm are specified and subsequently, when digits form. While the latter phase is controlled by enhancers centromeric to the HoxD cluster, we show here that the early phase requires enhancers located in the opposite telomeric gene desert. The transition between the two types of regulations involves a functional switch between two distinct topological domains, as reflected by a subset of genes mapping centrally into the cluster, which initially interact with the telomeric domain and subsequently shift to establish new contacts on the opposite side. This transition between two regulatory landscapes generates an intermediate area of low Hox dose developing into the wrist, the transition between our arms and our hands. This intriguing correspondence between genomic and morphological boundaries illustrates the mechanism underlying collinear Hox gene regulation in our developing appendages. Circular Chromosome Conformation Capture (4C seq) at the HoxD locus in developing proximal and distal limbs at E9.5 and E12.5
2013-06-07 | E-GEOD-45455 | biostudies-arrayexpress
Project description:During limb development, Hoxd genes are transcribed in two waves: Early on, when the arm and forearm are specified and subsequently, when digits form. While the latter phase is controlled by enhancers centromeric to the HoxD cluster, we show here that the early phase requires enhancers located in the opposite telomeric gene desert. The transition between the two types of regulations involves a functional switch between two distinct topological domains, as reflected by a subset of genes mapping centrally into the cluster, which initially interact with the telomeric domain and subsequently shift to establish new contacts on the opposite side. This transition between two regulatory landscapes generates an intermediate area of low Hox dose developing into the wrist, the transition between our arms and our hands. This intriguing correspondence between genomic and morphological boundaries illustrates the mechanism underlying collinear Hox gene regulation in our developing appendages. Chromatin ImmunoPrecipitation and Sequencing (ChIP-seq) of H3K27A in developing proximal and distal limbs at E9.5, E10.5 and E12.5
2013-06-07 | E-GEOD-45456 | biostudies-arrayexpress
Project description:During limb development, Hoxd genes are transcribed in two waves: Early on, when the arm and forearm are specified and subsequently, when digits form. While the latter phase is controlled by enhancers centromeric to the HoxD cluster, we show here that the early phase requires enhancers located in the opposite telomeric gene desert. The transition between the two types of regulations involves a functional switch between two distinct topological domains, as reflected by a subset of genes mapping centrally into the cluster, which initially interact with the telomeric domain and subsequently shift to establish new contacts on the opposite side. This transition between two regulatory landscapes generates an intermediate area of low Hox dose developing into the wrist, the transition between our arms and our hands. This intriguing correspondence between genomic and morphological boundaries illustrates the mechanism underlying collinear Hox gene regulation in our developing appendages. Chromatin ImmoPrecipitation on chip (Tiling array): Distribution of H3K4me3 and H3K27me3 in early limb buds at E9.5, E10.5 and proximal late limbs E12.5. Distribution of H3K27me3 in del(8-13) and del(8-13)/del(attP-TpSB3) E10.5 limb buds. Distribution of H3K27me3 in WT and homozygote del(Nsi-Atf2) (Montavon et al., 2011) forelimb autopods.
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Project description: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.
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Project description:In order to try and evaluate Hoxd transcript heterogeneity during limb development, we produced single-limb cell transcriptomes of different origins, to see whether the apparently homogenous behavior in Hox gene transcriptional program as observed upon large-scale analyses was confirmed at the cellular level. We report here thatHoxd genes transcripts are present in various combinations in different limb cells and discuss the importance of these results in our understanding of how Hoxd genes are regulated and how their global functions are achieved in these structures. Single-cells transcriptomes from Hoxd11::GFP forelimbs with micro-dissection of autopod and zeugopod at embryonic day 12 (E12.5).
2018-08-24 | GSE114748 | GEO
Project description:Cumulative in-cis mutagenesis in vivo reveals various functions for CTCF sites at the mouse Hoxd cluster [cHi-C]
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Project description:The emergence and evolution of digits was an essential step in the success of the tetrapod lineage. Amongst the key players, Hoxd genes were functionally co-opted in the developing digital plate, where they help organize growth and patterns. To understand both the evolutionary recruitment and transcriptional regulation of this genomic locus, we analyzed its architecture and chromatin status in developing digits, combined with a deletion approach in vivo. We show that the active and inactive parts of the gene cluster adopt opposite spatial configurations, corresponding to different chromatin domains. Active genes are contacted by several regulatory islands, located within a neighboring gene desert, which contribute quantitatively or qualitatively to the global transcriptional readout. We refer to this novel type of control as a ‘regulatory archipelago’ and discuss the value of this concept to understand both the morphological flexibility of tetrapod digits and the robustness of the underlying developmental process. Transcriptional activity at the Hoxd locus in developing limbs and brain at E12.5
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Project description:Analysis of gene expression in the distal forelimbs RNA-Seq polyA on transcripts extracted from the dissection of three pairs of embryonnic forelimbs at E12.5
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