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HOX13-dependent chromatin accessibility underlies the transition towards the digit development program[ATAC-Seq]

ABSTRACT: Pioneer factors are transcription factors able to recognize their target site even concealed in “closed” chromatin, eventually eliciting the switch to accessible targets for other transcription factors and the transcriptional machinery. As such, pioneer factors play a key role in switching cell fate. Here, we provide evidence that HOXA13 and HOXD13 (HOX13 hereafter), two transcription factors of the Hox family of developmental genes, act as pioneer factors in the developing limb. We show that Hox13 function is mandatory for switching a series of target loci to an accessible chromatin state, allowing the binding of other transcription factors. These target loci include an enhancer previously identified as essential for the pentadactyl state, providing evidence that the pioneer activity of HOX13 is key for digit patterning. Based on the data reported here and previous studies, we propose that, during the fin-to-limb transition, the implementation of digit-specific enhancer elements had required an ancestral pioneer function of the HOX13 TFs.

ORGANISM(S): Mus musculus

PROVIDER: GSE123481 | GEO | 2020/04/03

REPOSITORIES: GEO

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HOX13-dependent chromatin accessibility underlies the transition towards the digit development program[ChIP-seq]

Project description:Pioneer factors are transcription factors able to recognize their target site even concealed in “closed” chromatin, eventually eliciting the switch to accessible targets for other transcription factors and the transcriptional machinery. As such, pioneer factors play a key role in switching cell fate. Here, we provide evidence that HOXA13 and HOXD13 (HOX13 hereafter), two transcription factors of the Hox family of developmental genes, act as pioneer factors in the developing limb. We show that Hox13 function is mandatory for switching a series of target loci to an accessible chromatin state, allowing the binding of other transcription factors. These target loci include an enhancer previously identified as essential for the pentadactyl state, providing evidence that the pioneer activity of HOX13 is key for digit patterning. Based on the data reported here and previous studies, we propose that, during the fin-to-limb transition, the implementation of digit-specific enhancer elements had required an ancestral pioneer function of the HOX13 TFs.

2020-03-25 | GSE123480 | GEO

HOX13 activity reprograms cis-regulatory modules during digit development (RNA-Seq)

Project description:The combinatorial expression of the Hox genes along the body axes, referred to as the HOX code, is a major determinant of cell fate and plays a prevailing role in generating the animal body plan. In developing limb buds, the paralogous group 13 genes of the HoxA and HoxD clusters are essential for patterning the distal-most limb structures, the digits. Inactivation of HOXA13 and HOXD13 transcription factors (HOX13) leads to complete digit agenesis in mice, but how HOX13 regulate transcriptional outcomes and confer identity to the distal-most limb cells has remained elusive. Here we performed genome-wide profiling of HOX13 by chromatin immunoprecipitation and analyzed the transcriptome and chromatin state of wild type early and late-distal limb buds, as well as Hoxa13-/-;Hoxd13-/- compound mutant limb buds. Our results show that inactivation of HOX13 impairs the activation and repression of putative cis-regulatory modules specific to the late-distal limb cells. Loss of HOX13 also disrupts the specific, spatial patterning of gene expression along the proximal-distal axis of the developing limb buds. These results show that proper termination of the early limb transcriptional program and activation of the late-distal limb program are coordinated by the dual action of HOX13 on cis-regulatory modules.

2016-12-14 | GSE81357 | GEO

HOX13 activity reprograms cis-regulatory modules during digit development (ChIP-Seq)

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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

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HOX13 activity reprograms cis-regulatory modules during digit development

Project description:HOX13 activity reprograms cis-regulatory modules during digit development

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Evidence against tetrapod-wide digit identities and for a limited frame shift in bird wings

Project description:In crown group tetrapods, individual digits are homologized in relation to a pentadactyl ground plan. However, testing hypotheses of digit homology is challenging because it is unclear whether digits develop with distinct and conserved gene regulatory states. Here we show dramatic evolutionary dynamism in the gene expression profiles of digits, challenging the notion that five digit identities are conserved across amniotes. Transcriptomics of developing limbs shows diversity in the patterns of genetic differentiation of digits, although the anterior-most digit has a unique, conserved expression profile. Further, we identify a core set of transcription factors that are differentially expressed among the digits of amniote limbs; their spatial expression domains, however, vary between species. In light of these results, we reevaluate the frame shift hypothesis of avian wing evolution and conclude that only the anterior-most digit has shifted position, suggesting a 1,3,4 digit identity in the bird wing.

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HOX13-dependent chromatin accessibility underlies the transition towards the digit development program

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Project description:Shh signal mediated by Gli family of transcription factors regulates digit growth and patterning in early limb development. Shh expression in the posterior margin of the limb bud defines the zone of polarizing activity. However, much less is know about downstream targets that mediate Shh signal functions. In this dataset, we include the expression data obtained from dissected anterior and posterior halves of mouse limb bud respectively. These data are used to obtain 889 transcripts that were upregulated 1.3 fold or more in the posterior limb bud, and 1189 transcripts that were enriched in the anterior limb bud at 1.3 fold or more. Two samples were analyzed. We generate pairwise comparisons between anterior and posterior limb tissues. Genes with a fold-change ≥1.3 were selected.

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