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Clustering of tissue-specific sub-TADs accompanies the regulation of HoxA genes in developing limbs

ABSTRACT: HoxA genes exhibit central roles during development and causal mutations have been found in several human syndromes including limb malformation. Despite their importance, information on how these genes are regulated is lacking. Here, we report on the first identification of bona fide transcriptional enhancers controlling HoxA genes in developing limbs and show that these enhancers are grouped into distinct topological domains at the sub-megabase scale (sub-TADs). We provide evidence that target genes and regulatory elements physically interact with each other through contacts between sub-TADs rather than by the formation of discreet "DNA loops". Interestingly, there is no obvious relationship between the functional domains of the enhancers within the limb and how they are partitioned among the topological domains, suggesting that sub-TAD formation does not rely on enhancer activity. Moreover, we show that suppressing the transcriptional activity of enhancers does not abrogate their contacts with HoxA genes. Based on these data, we propose a model whereby chromatin architecture defines the functional landscapes of enhancers. From an evolutionary standpoint, our data points to the convergent evolution of HoxA and HoxD regulation in the fin-to-limb transition, one of the major morphological innovations in Vertebrates.

ORGANISM(S): Mus musculus

PROVIDER: GSE52483 | GEO | 2013/11/19

SECONDARY ACCESSION(S): PRJNA229082

REPOSITORIES: GEO

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Clustering of tissue-specific sub-TADs accompanies the regulation of HoxA genes in developing limbs

Project description:HoxA genes exhibit central roles during development and causal mutations have been found in several human syndromes including limb malformation. Despite their importance, information on how these genes are regulated is lacking. Here, we report on the first identification of bona fide transcriptional enhancers controlling HoxA genes in developing limbs and show that these enhancers are grouped into distinct topological domains at the sub-megabase scale (sub-TADs). We provide evidence that target genes and regulatory elements physically interact with each other through contacts between sub-TADs rather than by the formation of discreet "DNA loops". Interestingly, there is no obvious relationship between the functional domains of the enhancers within the limb and how they are partitioned among the topological domains, suggesting that sub-TAD formation does not rely on enhancer activity. Moreover, we show that suppressing the transcriptional activity of enhancers does not abrogate their contacts with HoxA genes. Based on these data, we propose a model whereby chromatin architecture defines the functional landscapes of enhancers. From an evolutionary standpoint, our data points to the convergent evolution of HoxA and HoxD regulation in the fin-to-limb transition, one of the major morphological innovations in Vertebrates. The chromatin binding of the RNA polymerase II and the sub-unit Med12 of the Mediator complexe were analysed by ChIP-sequencing mouse distal E11.5 forelimb. This approach allowed us to identify the position of limb-specific enhancers.

2013-11-19 | E-GEOD-52483 | biostudies-arrayexpress

Characterisation of the mouse alpha-globin sub-TAD 3' boundary in erythroid cells [NG Capture-C]

Project description:Mammalian genomes are subdivided into large (50-2000 kb) regions of chromatin referred to as Topologically Associating Domains (TADs or sub-TADs). Chromatin within an individual TAD contacts itself more frequently than with regions in surrounding TADs thereby directing enhancer-promoter interactions. In many cases, the borders of TADs are defined by convergently orientated boundary elements associated with CCCTC-binding factor (CTCF), which stabilises the cohesin complex on chromatin and prevents its translocation. This delimits chromatin loop extrusion which is thought to underlie the formation of TADs. However, not all CTCF-bound sites act as boundaries and, importantly, not all TADs are flanked by convergent CTCF sites. Here, we examined the CTCF binding sites within a ~70 kb sub-TAD containing the duplicated mouse α-like globin genes and their five enhancers (5’-R1-R2-R3-Rm-R4-α1-α2-3’). The 5’ border of this sub-TAD is defined by a pair of CTCF sites. Surprisingly, we show that deletion of the CTCF binding sites within and downstream of the α-globin locus leaves the sub-TAD largely intact. The predominant 3’ border of the sub-TAD is defined by a steep reduction in contacts: this corresponds to the transcribed α2-globin gene rather than the CTCF sites at the 3’-end of the sub-TAD. Of interest, the almost identical α1- and α2-globin genes interact differently with the enhancers, resulting in preferential expression of the proximal α1-globin gene which behaves as a partial boundary between the enhancers and the distal α2-globin gene. Together, these observations provide direct evidence that actively transcribed genes can behave as boundary elements.

2022-06-01 | GSE153208 | GEO

Characterisation of the mouse alpha-globin sub-TAD 3' boundary in erythroid cells [ATAC-seq]

2022-06-01 | GSE153207 | GEO

Characterisation of the mouse alpha-globin sub-TAD 3' boundary in erythroid cells [ChIP-seq]

2022-06-01 | GSE153206 | GEO

Characterisation of the mouse alpha-globin sub-TAD 3' boundary in erythroid cells [RNA-seq]

2022-06-01 | GSE153205 | GEO

A Switch Between Topological Domains Underlies HoxD Genes Collinearity in Mouse Limbs (ChIP-chip)

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.

2013-06-07 | E-GEOD-45454 | biostudies-arrayexpress

A Switch Between Topological Domains Underlies HoxD Genes Collinearity in Mouse Limbs (4C-Seq)

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

A Switch Between Topological Domains Underlies HoxD Genes Collinearity in Mouse Limbs (ChIP-Seq)

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

Disruptions of Topological Chromatin Domains Causes Pathogenic Rewiring of Gene-Enhancer Interactions [RNA-Seq]

Project description:Mammalian genomes are organized into megabase-scale topologically associated domains (TADs) that have been proposed to represent large regulatory units. Here we demonstrate that disruption of TADs can cause rewiring of long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome. RNA-seq profile of developing distal limbs of mutants and WT animals at E11.5

2015-05-08 | E-GEOD-66377 | biostudies-arrayexpress

Disruptions of Topological Chromatin Domains Causes Pathogenic Rewiring of Gene-Enhancer Interactions [4C-Seq-human]

Project description:Mammalian genomes are organized into megabase-scale topologically associated domains (TADs) that have been proposed to represent large regulatory units. Here we demonstrate that disruption of TADs can cause rewiring of long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome. Circular Chromosome Conformation Capture (4C seq) at the WNT6/IHH/EPHA4/PAX3 locus in human adult fibroblasts (HAF) of adult patients and controls

2015-05-08 | E-GEOD-66378 | biostudies-arrayexpress

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