Distal Limb Patterning Requires Modulation of cis-Regulatory Activities by HOX13

Sheth, Rushikesh; Barozzi, Iros; Langlais, David; Osterwalder, Marco; Nemec, Stephen; Carlson, Hanqian L.; Stadler, H. Scott; Visel, Axel; Drouin, Jacques; Kmita, Marie

doi:10.1016/j.celrep.2016.11.039

Cited by 80 publications

(149 citation statements)

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“…These genes-in particular Hox13-retroinhibit more anterior Hox genes (Denans et al 2015;Beccari et al 2016;Sheth et al 2016). In addition, they antagonize Cdx2 and more centrally located Hox genes in their task of axial stimulation by directly interfering with activation of the Wnt and Fgf pathways .…”

Section: A Link Between the Hox Clock And The Somitic Clock?mentioning

confidence: 99%

“…This topological switch in regulations is due in part to a retroactive negative effect of HOX13 proteins upon the activity of the 3 ′ TAD. This was shown by the genetic removal of the appropriate HOX13 proteins, which prevented the 3 ′ TAD from switching off; its enhancers continued to operate in most distal limb bud cells, where 5 ′ TAD enhancers should have normally operated Sheth et al 2016).…”

Section: Transcription Timing Vs Evolutionary Timingmentioning

confidence: 99%

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Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock

2017

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Collinear regulation of Hox genes in space and time has been an outstanding question ever since the initial work of Ed Lewis in 1978. Here we discuss recent advances in our understanding of this phenomenon in relation to novel concepts associated with large-scale regulation and chromatin structure during the development of both axial and limb patterns. We further discuss how this sequential transcriptional activation marks embryonic stem cell-like axial progenitors in mammals and, consequently, how a temporal genetic system is further translated into spatial coordinates via the fate of these progenitors. In this context, we argue the benefit and necessity of implementing this unique mechanism as well as the difficulty in evolving an alternative strategy to deliver this critical positional information.

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Section: A Link Between the Hox Clock And The Somitic Clock?mentioning

confidence: 99%

Section: Transcription Timing Vs Evolutionary Timingmentioning

confidence: 99%

Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock

2017

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“…Extended Data Fig.1). Reminiscent of the distribution of HOX13-bound loci in distal limbs 13 , the vast majority of HOXA11 ChIP-seq peaks are located at genomic regions distinct from transcriptional start site (TSS; Fig. 1c).…”

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confidence: 99%

HOX13-dependent chromatin accessibility modulates the target repertoires of the HOX factors

Desanlis

Kherdjemil

Mayran

et al. 2019

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Hox genes encode essential transcription factors that control patterning during embryonic development. Distinct combinations of nested Hox expression domains establish cell and tissue identities 1-3 . Consequently, spatial or temporal de-regulation of Hox genes can cause severe alterations of the body plan 3 . While HOX factors have very similar DNA binding motifs, their binding specificity is, in part, mediated by co-factors 4-6 . Yet, the interplay between HOX binding specificities and the cellular context remains largely elusive. To gain insight into this question, we took advantage of developing limbs for which the differential expression of Hox genes is well-characterized 7 . We show that the transcription factors HOXA13 and HOXD13 (hereafter referred as HOX13) allow another HOX factor, HOXA11, to bind loci initially assumed to be HOX13-specific. Importantly, HOXA11 is unable to bind these loci in distal limbs lacking HOX13 function indicating that HOX13 modulates HOXA11 target repertoire.In addition, we find that the HOX13 factors implement the distal limb developmental program by triggering chromatin opening, a defining property of pioneer factors 8,9 . Finally, single cell analysis of chromatin accessibility reveals that HOX13 factors pioneer chromatin opening in a lineage specific manner. Together, our data uncover a new mechanism underlying HOX binding specificity, whereby tissue-specific variations in the target repertoire of HOX factors rely, at least in part, on HOX13-dependent chromatin accessibility.

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“…Sheth et al. (Sheth et al., ) identified the limb target genes of HOXA13 and HOXD13, whose function is redundant in the autopodal development. They reported most of the target genes are common to both HOXA13 and HOXD13 and many of them are related to cartilage differentiation.…”

Section: Discussionmentioning

confidence: 99%

Hoxa13 regulates expression of common Hox target genes involved in cartilage development to coordinate the expansion of the autopodal anlage

et al. 2019

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To elucidate the role of Hox genes in limb cartilage development, we identified the target genes of HOXA11 and HOXA13 by ChIP‐Seq. The ChIP DNA fragment contained evolutionarily conserved sequences and multiple highly conserved HOX binding sites. A substantial portion of the HOXA11 ChIP fragment overlapped with the HOXA13 ChIP fragment indicating that both factors share common targets. Deletion of the target regions neighboring Bmp2 or Tshz2 reduced their expression in the autopod suggesting that they function as the limb bud‐specific enhancers. We identified the Hox downstream genes as exhibiting expression changes in the Hoxa13 knock out (KO) and Hoxd11‐13 deletion double mutant (Hox13 dKO) autopod by Genechip analysis. The Hox downstream genes neighboring the ChIP fragment were defined as the direct targets of Hox. We analyzed the spatial expression pattern of the Hox target genes that encode two different categories of transcription factors during autopod development and Hox13dKO limb bud. (a) Bcl11a, encoding a repressor of cartilage differentiation, was expressed in the E11.5 autopod and was substantially reduced in the Hox13dKO. (b) The transcription factors Aff3, Bnc2, Nfib and Runx1t1 were expressed in the zeugopodal cartilage but not in the autopod due to the repressive or relatively weak transcriptional activity of Hox13 at E11.5. Interestingly, the expression of these genes was later observed in the autopodal cartilage at E12.5. These results indicate that Hox13 transiently suspends the cartilage differentiation in the autopodal anlage via multiple pathways until establishing the paddle‐shaped structure required to generate five digits.

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Distal Limb Patterning Requires Modulation of cis-Regulatory Activities by HOX13

Cited by 80 publications

References 64 publications

Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock

Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock

HOX13-dependent chromatin accessibility modulates the target repertoires of the HOX factors

Hoxa13 regulates expression of common Hox target genes involved in cartilage development to coordinate the expansion of the autopodal anlage

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