Mechanisms of Specificity for Hox Factor Activity

Zandvakili, Arya; Gebelein, Brian

doi:10.3390/jdb4020016

Cited by 30 publications

(22 citation statements)

References 150 publications

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“…Their differential expression along the main body axis establishes positional information that instructs cells about their fate, ultimately generating morphological diversity [1][2][3] . The wide-range of HOX-dependent genetic programs is intriguing considering that the various HOX TFs have similar DNA-binding properties 6 . Several studies uncovered the relevance of co-factors, notably the PBX/Exd family of TFs, in increasing DNAbinding specificity [4][5][6] .…”

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confidence: 99%

“…The wide-range of HOX-dependent genetic programs is intriguing considering that the various HOX TFs have similar DNA-binding properties 6 . Several studies uncovered the relevance of co-factors, notably the PBX/Exd family of TFs, in increasing DNAbinding specificity [4][5][6] . Analyses using micromass culture from primary mesenchymal limb bud cells revealed that group 11 and 13 Hox genes cluster in the same subgroup 10 despite the fact that HOXA11/HOXD11 are required for the zeugopod (forearm) developmental program 11 while HOXA13 and HOXD13 are mandatory for digit development 12 (Fig.…”

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

Desanlis

Kherdjemil

Mayran

et al. 2019

Preprint

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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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confidence: 99%

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

Desanlis

Kherdjemil

Mayran

et al. 2019

Preprint

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“…A long-standing question in developmental biology has been how homologous transcription factors with similar DNA binding domains produce different activities. The Hox homeodomain factors are exemplars of such protein families, as each Hox factor binds similar AT-rich sequences in vitro, yet drives distinct developmental programs in vivo [7]. One advance in answering this paradox was to show that Hox proteins have different binding preferences in the presence of Exd and Hth [11][12][13].…”

Section: Discussionmentioning

confidence: 99%

“…While the number of Hox genes varies between animals, Hox genes share in common the property of instructing cells to adopt a "regional" (or "segment") identity within the organism by regulating the expression of downstream target genes [3]. Recent genomic studies have indicated Hox factors affect the expression of hundreds of downstream target genes [4][5][6][7]. Since each region or segment under the control of a specific Hox factor is composed of many cell-and tissue-types, these findings present two fundamental challenges in understanding how Hox genes sculpt the body plan: First, what makes one Hox factor different from another to specify distinct embryonic regions during development?…”

Section: Introductionmentioning

confidence: 99%

Thecis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements inDrosophila

Zandvakili

Uhl

Campbell

et al. 2018

Preprint

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Hox genes encode a family of transcription factors that, despite having similar in vitro DNA binding preferences, regulate distinct genetic programs along the metazoan anterior-posterior axis. To better define mechanisms of Hox specificity, we compared and contrasted the ability of abdominal Hox factors to regulate two cis-regulatory elements within the Drosophila embryo. Both the Ultrabithorax (Ubx) and Abdominal-A (Abd-A) Hox factors form cooperative complexes with the Extradenticle (Exd) and Homothorax (Hth) transcription factors to repress the distal-less leg selector gene via the DCRE, whereas only Abd-A interacts with Exd and Hth on the RhoA element to activate a rhomboid serine protease gene that stimulates Epidermal Growth Factor secretion.By swapping binding sites between these elements, we found that the RhoA Exd/Hth/Hox site configuration that mediates Abd-A specific activation can also convey transcriptional repression by both Ubx and Abd-A when placed into the DCRE, but only in one orientation. We further show that the orientation and spacing of Hox sites relative to additional transcription factor binding sites within the RhoA and DCRE elements is critical to mediate appropriate cell-and segment-specific output. These results indicate that the interaction between Hox, Exd, and Hth neither determines activation vs repression specificity nor defines Ubx vs Abd-A specificity. Instead the precise integration of Hox sites with additional TF inputs is required for accurate transcriptional output.Taken together, these studies provide new insight into the mechanisms of Hox target and regulatory specificity as well as the constraints placed on regulatory elements to convey appropriate outputs. Author SummaryThe Hox genes encode a family of transcription factors that give cells within each region along the developing body plan a unique identity in animals from worms to mammals. Surprisingly, however, most of the Hox factors bind the same or highly similar DNA sequences. These findings raise a paradox: How can proteins that have highly similar DNA binding properties perform different functions in the animal by regulating different sets of target genes? In this study, we address this question by studying how two Hox factors regulate the expression of target genes that specify leg development and the making of liver-like cells in the developing fly. By comparing and contrasting how Hox target genes are activated and/or repressed, we found that the same Hox binding sites can mediate either activation or repression in a manner that depends upon context. In addition, we found that a Hox binding site that is normally regulated by only one Hox factor, can also be used by more than one Hox factor swapped into another target gene. These findings indicate that the specificity of a Hox factor to regulate target genes does not rely solely upon DNA binding specificity but also requires regulatory specificity.

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“…In the case of Drosophila, the phosphorylation state of the HOX protein is crucial for its transcriptional activity (Berry & Gehring, 2000). In addition, the presence of the co-factors that modulate transcriptional activity of Drosophila HOX was reported (reviewed in Zandvakili & Gebelein, 2016). Since these mechanisms related to HOXA13 have yet to be elucidated, research into this issue will be a topic for future studies.…”

Section: Hox13 Regulates Cartilage Differentiation In a Dual Mannermentioning

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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Mechanisms of Specificity for Hox Factor Activity

Cited by 30 publications

References 150 publications

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

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

Thecis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements inDrosophila

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

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