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

Ines Desanlis, Yacine Kherdjemil, Alexandre Mayran, Yasser Bouklouch, Claudia Gentile, Rushikesh Sheth, Rolf Zeller, Jacques Drouin, Marie Kmita
doi: https://doi.org/10.1101/789875
Ines Desanlis
1Genetics and Development Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
2Département de Médecine, Université de Montréal, Montréal, QC, Canada
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Yacine Kherdjemil
1Genetics and Development Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
2Département de Médecine, Université de Montréal, Montréal, QC, Canada
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Alexandre Mayran
3Molecular Genetics Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
4EPFL, School of Life Sciences, 1015 Lausanne, Switzerland
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Yasser Bouklouch
1Genetics and Development Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
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Claudia Gentile
1Genetics and Development Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
6Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada
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Rushikesh Sheth
5Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
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Rolf Zeller
5Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
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Jacques Drouin
3Molecular Genetics Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
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Marie Kmita
1Genetics and Development Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
2Département de Médecine, Université de Montréal, Montréal, QC, Canada
6Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada
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  • For correspondence: Marie.Kmita@ircm.qc.ca
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ABSTRACT

Hox genes encode essential transcription factors that control patterning during embryonic development. Distinct combinations of nested Hox expression domains establish cell and tissue identities1–3. Consequently, spatial or temporal de-regulation of Hox genes can cause severe alterations of the body plan3. While HOX factors have very similar DNA binding motifs, their binding specificity is, in part, mediated by co-factors4–6. 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-characterized7. 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 factors8,9. 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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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted October 02, 2019.
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HOX13-dependent chromatin accessibility modulates the target repertoires of the HOX factors
Ines Desanlis, Yacine Kherdjemil, Alexandre Mayran, Yasser Bouklouch, Claudia Gentile, Rushikesh Sheth, Rolf Zeller, Jacques Drouin, Marie Kmita
bioRxiv 789875; doi: https://doi.org/10.1101/789875
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HOX13-dependent chromatin accessibility modulates the target repertoires of the HOX factors
Ines Desanlis, Yacine Kherdjemil, Alexandre Mayran, Yasser Bouklouch, Claudia Gentile, Rushikesh Sheth, Rolf Zeller, Jacques Drouin, Marie Kmita
bioRxiv 789875; doi: https://doi.org/10.1101/789875

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