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A TAD boundary at the HoxD locus segregates opposing limb regulatory landscapes and their target genes [Hi-C]

ABSTRACT: The mammalian HoxD cluster is positioned at the boundary between two topologically associating domains (TADs), each of them matching a distinct, enhancer-rich regulatory landscape. During limb development, the telomeric TAD controls the early phase of Hoxd gene transcription in future forearm cells, whereas the centromeric TAD subsequently regulates transcription of more posterior Hoxd genes in presumptive digit cells. The TAD boundary is essential as it prevents the terminal Hoxd13 gene to respond to potent forearm enhancers, thereby allowing the formation of proper proximal limb structures. Here we apply chromosome conformation capture onto embryonic proximal and distal limb bud cells micro-dissected from a set of nested deletions involving part- or all- of this boundary region to try to understand the nature and function of this CTCF- and cohesin-rich DNA region. We document a progressive release of the boundary effect, allowing for inter-TAD contacts to be established, which were favoured by the functional status of the newly accessed enhancers. However, the boundary was highly resilient and only a 400kb large deletion including the whole gene cluster was eventually able to merge the two neighbouring TADs into a single structure. We propose that the whole HoxD cluster is a dynamic transcriptional boundary, showing slight variations depending on both the transcriptional status and the ontogenetic context

ORGANISM(S): Mus musculus

PROVIDER: GSE101715 | GEO | 2017/12/22

SECONDARY ACCESSION(S): PRJNA395244

REPOSITORIES: GEO

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A TAD boundary at the HoxD locus segregates opposing limb regulatory landscapes and their target genes [ChIP-Seq]

Project description:The mammalian HoxD cluster is positioned at the boundary between two topologically associating domains (TADs), each of them matching a distinct, enhancer-rich regulatory landscape. During limb development, the telomeric TAD controls the early phase of Hoxd gene transcription in future forearm cells, whereas the centromeric TAD subsequently regulates transcription of more posterior Hoxd genes in presumptive digit cells. The TAD boundary is essential as it prevents the terminal Hoxd13 gene to respond to potent forearm enhancers, thereby allowing the formation of proper proximal limb structures. Here we apply chromosome conformation capture onto embryonic proximal and distal limb bud cells micro-dissected from a set of nested deletions involving part- or all- of this boundary region to try to understand the nature and function of this CTCF- and cohesin-rich DNA region. We document a progressive release of the boundary effect, allowing for inter-TAD contacts to be established, which were favoured by the functional status of the newly accessed enhancers. However, the boundary was highly resilient and only a 400kb large deletion including the whole gene cluster was eventually able to merge the two neighbouring TADs into a single structure. We propose that the whole HoxD cluster is a dynamic transcriptional boundary, showing slight variations depending on both the transcriptional status and the ontogenetic context

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Project description:In tetrapods, the HoxD gene cluster is critical for proper limb formation. In the emerging limb buds, different sub-groups of Hoxd genes respond first to a proximal regulatory signal, then to a distal signal that organizes digits. These two regulations emanate from the two TADs flanking HoxD, both containing a range of appropriate enhancer sequences. The telomeric TAD (T-DOM) contains several regulatory elements controlling Hoxd genes, initially in a temporal manner and then in the proximal presumptive forearm. T-DOM is divided into two sub-TADs separated by a CTCF-rich boundary defining two regulatory modules with most limb enhancers concentrated in the more distant module. In order to understand the importance of this regulatory topology to elicit a precise Hoxd gene transcription in time and space, we both deleted or inverted this sub-TAD boundary and eliminated the CTCF binding sites. These perturbations caused a time delay in gene activation, which was subsequently resumed. We then inverted the entire T-DOM to change the respective position of the two sub-TADs, which concomitantly introduced a TAD boundary between HoxD and the inverted T-DOM. This re-arrangement had a stronger impact on the early expression and flattened the Hoxd mRNAs levels. The latter effect was rescued by re-granting access to the enhancers upon deletion of the ectopic boundary. These results highlight the importance of regulatory topologies in the temporal control of gene expression. We also show that, along with time, the affinity of enhancers to find their natural target genes can overcome the presence of both a strong TAD border, and an unfavourable orientation of CTCF sites.

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Chromatin topology and the timing of enhancer function at the HoxD locus [ChIP-seq]

Project description:The HoxD gene cluster is critical for proper limb formation in tetrapods. In the emerging limb buds, different sub-groups of Hoxd genes respond first to a proximal regulatory signal, then to a distal signal that organizes digits. These two regulations are exclusive from one another and emanate separately from two TADs flanking HoxD, both containing a range of appropriate enhancer sequences. The telomeric TAD (T-DOM) contains several enhancers active in presumptive forearm cells and is divided into two sub-TADs separated by a CTCF-rich boundary, which defines two regulatory sub-modules. To understand the importance of this particular regulatory topology to control Hoxd gene transcription in time and space, we either deleted or inverted this sub-TAD boundary, eliminated the CTCF binding sites or inverted the entire T-DOM to exchange the respective positions of the two sub-TADs. The effects of such perturbations on the transcriptional regulation of Hoxd genes illustrates the requirement of this regulatory topology for the precise timing of gene activation. However, the spatial distribution of transcripts is eventually resumed, showing that the presence of enhancers sequences, rather than either their exact topology or a particular chromatin architecture, is the key factor. We also show that the affinity of enhancers to find their natural target genes can overcome the presence of both a strong TAD border and an unfavourable orientation of CTCF sites.

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Chromatin topology and the timing of enhancer function at the HoxD locus [RNA-seq]

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2017-07-12 | GSE98861 | GEO

A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus

Project description:During vertebrate limb development, Hoxd genes are regulated following a bimodal strategy involving two topologically associating domains (TADs) located on either side of the gene cluster. These regulatory landscapes alternatively control different subsets of Hoxd targets, first into the arm and, subsequently, into the digits. We studied the transition between these two global regulations, a switch that correlates with the positioning of the wrist, which articulates these two main limb segments. We show that the HOX13 proteins themselves help switch off the telomeric TAD, likely through a global repressive mechanism. At the same time, they directly interact with distal enhancers to sustain the activity of the centromeric TAD, thus explaining both the sequential and exclusive operating processes of these two regulatory domains. We propose a model whereby the activation of Hox13 gene expression in distal limb cells both interrupts the proximal Hox gene regulation and re-enforces the distal regulation. In the absence of HOX13 proteins, a proximal limb structure grows without any sign of wrist articulation, likely related to an ancestral fish-like condition.

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A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus

2016-05-19 | GSE79351 | GEO

Impact of genome architecture upon the functional activation and repression of Hox regulatory landscapes [RNA-seq]

Project description:The spatial organization of the mammalian genome is complex and relies upon the formation of chromatin domains of various scales. At the level of gene regulation in cis, collections of enhancer sequences define large regulatory landscapes that usually match with the presence of topologically associating domains (TADs). These domains are largely determined by bound CTCF molecules and often contain ranges of enhancers displaying similar or related tissue specificity, suggesting that in some cases such domains may act as coherent regulatory units, with a global on or off state. By using the HoxD gene cluster as a paradigm, we investigated the effect of large genomic rearrangements affecting the two TADs flanking this locus, including their fusion into a single chromatin domain. We show that, within a single hybrid TAD, the activation of both proximal and distal limb enhancers initially positioned in either TADs globally occurred as when both TADs are intact. We also show that the timely implementation of distal limb enhancers depends on whether or not target genes had previously responded to proximal enhancers, due to the presence or absence of H3K27me3 marks. From this work, we conclude that antagonistic limb proximal and distal enhancers can exert their specificities when positioned into the same TAD and in the absence of their genuine target genes. We also conclude that removing these target genes reduced the coverage of a regulatory landscape by chromatin marks associated with silencing and thus prolonged its activity in time. Since Polycomb group proteins are mainly recruited at the Hox gene cluster, our results suggest that Polycomb Repressive Complex 2 (PRC2) can extend its coverage to far-cis regulatory sequences as long as confined to the neighboring TAD structure.

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