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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE81357 | GEO | 2016/12/14

SECONDARY ACCESSION(S): PRJNA321344

REPOSITORIES: GEO

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HOX13 activity reprograms cis-regulatory modules during digit development (ChIP-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 | GSE81356 | GEO

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Project description:Limb patterning relies in a large part on the function of the Hox family of developmental genes. While the differential expression of Hox genes shifts from the anterior-posterior (A-P) to the proximal-distal (P-D) axis around embryonic day 11 (E11), whether this shift coincides with a more global change of P-D versus A-P patterning program remains unclear. By performing and analyzing the transcriptome of the developing limb bud from E10.5 to E12.5, at single cell resolution, we have uncovered transcriptional trajectories which revealed a general switch from A-P to P-D genetic program between E10.5 and E11.5. Interestingly, the transcriptional trajectories at E10.5 all end with cells expressing either proximal or distal markers suggesting a progressive acquisition of P-D identity. Moreover, we observed that distally expressed Hox genes, namely Hoxa13 and Hoxd13, act as a key determinant for P-D patterning as their transcriptional control results in their distal restricted expression, which in turn restricts Hoxa11 in the proximal limb bud domain, in progenitor cells of the zeugopod. Finally, we identified three categories of genes expressed in the distal limb mesenchyme characterized by distinct temporal expression dynamics. As anticipated from previous results, HOX13 binding was observed within or in the neighborhood of several of these genes consistent with previous evidence suggesting that the transition from the early/proximal to the late/distal transcriptome of the limb mesenchyme largely relies on HOX13 function.

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Project description:The free limb is subdivided into three anatomical domains along the proximodistal axis: the stylopod, zeugopod and autopod. These domains possess a specific number and pattern of the bones and each bone possesses unique morphology and length. During limb development, the mesenchymal cells of limb bud first forms precartilaginous aggregates which eventually grow and differentiate into the limb cartilage. Expression of Hox genes belonging to the Abd-B family, Hox9-13, is closely related to the anatomical domains of the limb bones and crucial for controlling morphogenesis and patterning of the limb cartilage. Hoxa13 and Hoxd13 are expressed in the autopodal mesenchyme and double KO mice have smaller autopods during the embryonic stage and a fan-shaped cartilage develops instead of the normal five digits. Thus, Hoxa13 and Hoxd13 are crucial for the cartilage patterning in the autopod. Since Hox encodes a transcription factor, Hox target genes function in region/compartment-specific formation of the precartilaginous condensation, cellular differentiation and proliferation of the cartilage. We used microarray to identified downstream genes of Hox13 in the autopod as exhibiting changes in the expression in the Hox13dKO mutant embryos.

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DBX2 REGULATION IN LIMBS SUGGESTS INTER-TAD SHARING OF ENHANCERS [4C-Seq]

Project description:During tetrapod limb development, the HOXA13 and HOXD13 transcription factors are critical for the emergence and organization of the autopods, the most distal aspect where digits will develop. Since previous work had suggested that the Dbx2 gene is a target of these factors, we set up to analyze in detail this potential regulatory interaction. We used a chromatin conformation capture approach (4Cseq) to characterize the regulatory domain and interactions of the transcription factor Dbx2 and of its neighboring genes Nell2 and Ano6 in distal and/ or proximal forelimbs of E12 mouse embryos. In particular, we analyzed their interaction with distal limb specific regulatory elements (DLE1 and DLE2) by the analysis of H2K27ac coverages (Beccari et al 2016) and Hoxa13/Hoxd13 binding (Sheth R et al 2016). We report that Dbx2, Nell2 and Ano6 are expressed in distal limb buds and are controlled by the same enhancers located close to Dbx2. As the Nell2 and Ano6 genes are localized into two different topologically associating domains (TADs) flanking the Dbx2 locus, we conclude that these enhancers can overcome TAD boundaries in either direction, to co-regulate a set of genes located in distinct chromatin domains.

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