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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE161376 | GEO | 2021/01/23

REPOSITORIES: GEO

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DBX2 REGULATION IN LIMBS SUGGESTS INTER-TAD SHARING OF ENHANCERS [HiC reanalysis]

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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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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