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

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 Gallus gallus

PROVIDER: GSE161378 | GEO | 2021/01/23

REPOSITORIES: GEO

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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.

2021-01-23 | GSE161376 | GEO

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

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

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

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Alteration of the gene expression profile in the Hox13dKO

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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Genome-wide mapping of Hoxa11 and Hoxa13 binding sites in the limb bud

Project description:Hox genes control domain specific cartilage pattern formation along the proximodistal axis. Hoxa11 and Hoxd11 (Hox11) show overlapping expression in the mesenchyme of the zeugopod and regulate cartilage growth and differentiation. Hoxa13 and Hoxd13 (Hox13) are expressed in the autopodal mesenchyme and are crucial for the autopodal cartilage patterning. Since both Hox11 and Hox13 are involved in the limb cartilage development, they may share the target genes. To identify common target genes among the Hoxa11 and Hoxa13, we performed ChIP-Seq analysis using specific antibody.

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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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Transcriptional profiling by RNA-seq in Dbx2-overexpressing cultures of adult neural progenitors

Project description:In selected tissutal niches of the adult mouse brain, such as the subventricular zone (SVZ) underlying the lateral ventricles, neurogenesis persists thanks to a population of quiescent neural stem cells, which can be activated (aNSCs) by extrinsic stimuli to initiate proliferation and generate a neurogenic lineage consisting of transit amplifying progenitors (TAPs), neuroblasts (NBs) and newborn neurons. This process is markedly reduced during aging, which might contribute to the cognitive decline of elderly subjects. Recent studies suggest that the aged niche environment may decrease the pool of proliferating neural/stem progenitor cells (NSPCs), and hence adult neurogenesis, by causing transcriptomic changes that favour NSC quiescence over activation. The transcription factors that mediate these changes, however, remain largely unclear. We previously found that the homeobox gene Dbx2 is upregulated in NSPCs of the aged mouse SVZ and can inhibit the growth of young adult NSPC cultures. Here, we show that Dbx2 expression is downregulated by Epidermal Growth Factor Receptor signalling, which promotes NSPC proliferation and decreases in the aged SVZ. By means of transgenic NSPC lines, we also show that Dbx2 inhibits NSPC proliferation by hindering the G1/S and the G2/M transition. Furthermore, we exploit RNA sequencing of transgenic NSPCs to elucidate the transcriptional networks modulated by Dbx2. Among the top hits, we report the downregulation of several gene categories implicated in cell cycle progression. Accordingly, we find that Dbx2 function is negatively correlated with the transcriptional signatures of proliferative NSPCs (aNSCs, TAPs and early NBs). Altogether, these results point to Dbx2 as a potential molecular node relaying the extracellular anti-neurogenic input of the aged niche to the NSPC transcriptome.

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GLI3 Controls the Proliferative Expansion of Digit Progenitors and Exit toward Chondrogenesis to Constrain the Autopod to Pentadactyly

Project description:The transcriptome of the anterior handplates of mouse limb buds of Gli3 constitutive and Hoxa13-Cre Gli3 conditional mutant embryos was compared to the transcriptome of limb buds of wild type and Gli3 heterozygote embryos at embryonic day E11.75. All samples carried one copy of the Hoxa13-Cre allele.

2012-03-01 | E-MEXP-3495 | biostudies-arrayexpress

Mesomelic Dysplasias Associated With The HOXD Locus Are Caused By Regulatory Reallocations [ChIP-Seq]

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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