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Title: The constrained architecture of mammalian Hox gene clusters

Abstract

In many animal species with a bilateral symmetry, Hox genes are clustered either at one or at several genomic loci. This organization has a functional relevance, as the transcriptional control applied to each gene depends upon its relative position within the gene cluster. It was previously noted that vertebrate Hox clusters display a much higher level of genomic organization than their invertebrate counterparts. The former are always more compact than the latter, they are generally devoid of repeats and of interspersed genes, and all genes are transcribed by the same DNA strand, suggesting that particular factors constrained these clusters toward a tighter structure during the evolution of the vertebrate lineage. Here, we investigate the importance of uniform transcriptional orientation by engineering several alleles within the HoxD cluster, such as to invert one or several transcription units, with or without a neighboring CTCF site. We observe that the association between the tight structure of mammalian Hoxclusters and their regulation makes inversions likely detrimental to the proper implementation of this complex genetic system. We propose that the consolidation of Hox clusters in vertebrates, including transcriptional polarity, evolved in conjunction with the emergence of global gene regulation via the flanking regulatory landscapes, tomore » optimize a coordinated response of selected subsets of target genes in cis.« less

Authors:
ORCiD logo [1];  [1]; ORCiD logo [1];  [2];  [2];  [1];  [2];  [3]
  1. Federal Inst. of Technology, Lausanne (Switzerland)
  2. Univ. of Geneva (Switzerland)
  3. Federal Inst. of Technology, Lausanne (Switzerland); Univ. of Geneva (Switzerland); Collège de France, Paris (France)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); European Research Council (ERC)
OSTI Identifier:
1560602
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 116; Journal Issue: 27; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Hox; CTCF; CRISPR-Cas9; transcription; Polycomb

Citation Formats

Darbellay, Fabrice, Bochaton, Célia, Lopez-Delisle, Lucille, Mascrez, Bénédicte, Tschopp, Patrick, Delpretti, Saskia, Zakany, Jozsef, and Duboule, Denis. The constrained architecture of mammalian Hox gene clusters. United States: N. p., 2019. Web. doi:10.1073/pnas.1904602116.
Darbellay, Fabrice, Bochaton, Célia, Lopez-Delisle, Lucille, Mascrez, Bénédicte, Tschopp, Patrick, Delpretti, Saskia, Zakany, Jozsef, & Duboule, Denis. The constrained architecture of mammalian Hox gene clusters. United States. doi:10.1073/pnas.1904602116.
Darbellay, Fabrice, Bochaton, Célia, Lopez-Delisle, Lucille, Mascrez, Bénédicte, Tschopp, Patrick, Delpretti, Saskia, Zakany, Jozsef, and Duboule, Denis. Mon . "The constrained architecture of mammalian Hox gene clusters". United States. doi:10.1073/pnas.1904602116. https://www.osti.gov/servlets/purl/1560602.
@article{osti_1560602,
title = {The constrained architecture of mammalian Hox gene clusters},
author = {Darbellay, Fabrice and Bochaton, Célia and Lopez-Delisle, Lucille and Mascrez, Bénédicte and Tschopp, Patrick and Delpretti, Saskia and Zakany, Jozsef and Duboule, Denis},
abstractNote = {In many animal species with a bilateral symmetry, Hox genes are clustered either at one or at several genomic loci. This organization has a functional relevance, as the transcriptional control applied to each gene depends upon its relative position within the gene cluster. It was previously noted that vertebrate Hox clusters display a much higher level of genomic organization than their invertebrate counterparts. The former are always more compact than the latter, they are generally devoid of repeats and of interspersed genes, and all genes are transcribed by the same DNA strand, suggesting that particular factors constrained these clusters toward a tighter structure during the evolution of the vertebrate lineage. Here, we investigate the importance of uniform transcriptional orientation by engineering several alleles within the HoxD cluster, such as to invert one or several transcription units, with or without a neighboring CTCF site. We observe that the association between the tight structure of mammalian Hoxclusters and their regulation makes inversions likely detrimental to the proper implementation of this complex genetic system. We propose that the consolidation of Hox clusters in vertebrates, including transcriptional polarity, evolved in conjunction with the emergence of global gene regulation via the flanking regulatory landscapes, to optimize a coordinated response of selected subsets of target genes in cis.},
doi = {10.1073/pnas.1904602116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 27,
volume = 116,
place = {United States},
year = {2019},
month = {6}
}

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Works referenced in this record:

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The HoxD cluster is a dynamic and resilient TAD boundary controlling the segregation of antagonistic regulatory landscapes
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The rise and fall of Hox gene clusters
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Cdx and Hox Genes Differentially Regulate Posterior Axial Growth in Mammalian Embryos
journal, October 2009


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journal, July 2014


Ciona intestinalis Hox gene cluster: Its dispersed structure and residual colinear expression in development
journal, October 2004

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CTCF binding landscape in jawless fish with reference to Hox cluster evolution
journal, July 2017


    Works referencing / citing this record:

    Hox and HOM: Homologous gene clusters in insects and vertebrates
    journal, May 1989


    The murine and Drosophila homeobox gene complexes have common features of organization and expression
    journal, May 1989


    Colinearity and functional hierarchy among genes of the homeotic complexes
    journal, October 1994


    Multiple Mechanisms Confining RNA Polymerase II Ubiquitylation to Polymerases Undergoing Transcriptional Arrest
    journal, June 2005


    Multiple Enhancers Regulate Hoxd Genes and the Hotdog LncRNA during Cecum Budding
    journal, October 2013


    Cdx and Hox Genes Differentially Regulate Posterior Axial Growth in Mammalian Embryos
    journal, October 2009


    Functional Analysis of CTCF During Mammalian Limb Development
    journal, December 2010


    Tail Bud Progenitor Activity Relies on a Network Comprising Gdf11, Lin28, and Hox13 Genes
    journal, February 2019


    RNA Polymerase II Collision Interrupts Convergent Transcription
    journal, November 2012


    Interactions between JARID2 and Noncoding RNAs Regulate PRC2 Recruitment to Chromatin
    journal, January 2014


    Regulatory Interactions between RNA and Polycomb Repressive Complex 2
    journal, July 2014


    RNA Polymerase Collision versus DNA Structural Distortion: Twists and Turns Can Cause Break Failure
    journal, May 2016


    HOM-C evolution in Drosophila: is there a need for Hox gene clustering?
    journal, February 2007


    A regulatory ‘landscape effect’ over the HoxD cluster
    journal, March 2011


    A gene complex controlling segmentation in Drosophila
    journal, December 1978


    Targeted inversion of a polar silencer within the HoxD complex re-allocates domains of enhancer sharing
    journal, December 2000

    • Kmita, Marie; Kondo, Takashi; Duboule, Denis
    • Nature Genetics, Vol. 26, Issue 4
    • DOI: 10.1038/82593

    The amphioxus genome and the evolution of the chordate karyotype
    journal, June 2008

    • Putnam, Nicholas H.; Butts, Thomas; Ferrier, David E. K.
    • Nature, Vol. 453, Issue 7198
    • DOI: 10.1038/nature06967

    The axolotl genome and the evolution of key tissue formation regulators
    journal, January 2018

    • Nowoshilow, Sergej; Schloissnig, Siegfried; Fei, Ji-Feng
    • Nature, Vol. 554, Issue 7690
    • DOI: 10.1038/nature25458

    A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element
    journal, August 2014

    • Herzog, Veronika A.; Lempradl, Adelheid; Trupke, Johanna
    • Nature Genetics, Vol. 46, Issue 9
    • DOI: 10.1038/ng.3058

    CTCF: an architectural protein bridging genome topology and function
    journal, March 2014

    • Ong, Chin-Tong; Corces, Victor G.
    • Nature Reviews Genetics, Vol. 15, Issue 4
    • DOI: 10.1038/nrg3663

    Promiscuous RNA binding by Polycomb repressive complex 2
    journal, September 2013

    • Davidovich, Chen; Zheng, Leon; Goodrich, Karen J.
    • Nature Structural & Molecular Biology, Vol. 20, Issue 11
    • DOI: 10.1038/nsmb.2679

    Hagfish and lamprey Hox genes reveal conservation of temporal colinearity in vertebrates
    journal, April 2018

    • Pascual-Anaya, Juan; Sato, Iori; Sugahara, Fumiaki
    • Nature Ecology & Evolution, Vol. 2, Issue 5
    • DOI: 10.1038/s41559-018-0526-2

    CTCF binding landscape in jawless fish with reference to Hox cluster evolution
    journal, July 2017


    Ciona intestinalis Hox gene cluster: Its dispersed structure and residual colinear expression in development
    journal, October 2004

    • Ikuta, T.; Yoshida, N.; Satoh, N.
    • Proceedings of the National Academy of Sciences, Vol. 101, Issue 42
    • DOI: 10.1073/pnas.0401389101

    Transcriptional collision between convergent genes in budding yeast
    journal, June 2002

    • Prescott, E. M.; Proudfoot, N. J.
    • Proceedings of the National Academy of Sciences, Vol. 99, Issue 13
    • DOI: 10.1073/pnas.132270899

    Directing traffic on DNA—How transcription factors relieve or induce transcriptional interference
    journal, January 2017


    CTCF-mediated topological boundaries during development foster appropriate gene regulation
    journal, December 2016

    • Narendra, Varun; Bulajić, Milica; Dekker, Job
    • Genes & Development, Vol. 30, Issue 24
    • DOI: 10.1101/gad.288324.116

    The HoxD cluster is a dynamic and resilient TAD boundary controlling the segregation of antagonistic regulatory landscapes
    journal, November 2017

    • Rodríguez-Carballo, Eddie; Lopez-Delisle, Lucille; Zhan, Ye
    • Genes & Development, Vol. 31, Issue 22
    • DOI: 10.1101/gad.307769.117

    Hox11 paralogous genes are essential for metanephric kidney induction
    journal, June 2002


    A Switch Between Topological Domains Underlies HoxD Genes Collinearity in Mouse Limbs
    journal, June 2013


    CTCF and Cohesin in Genome Folding and Transcriptional Gene Regulation
    journal, August 2016


    Cellular dynamics underlying regeneration of appropriate segment number during axolotl tail regeneration
    journal, December 2015

    • Vincent, Carr D.; Rost, Fabian; Masselink, Wouter
    • BMC Developmental Biology, Vol. 15, Issue 1
    • DOI: 10.1186/s12861-015-0098-1

    The rise and fall of Hox gene clusters
    journal, June 2007


    Distinct Roles and Regulations for Hoxd Genes in Metanephric Kidney Development
    journal, January 2007


    Transcriptional Interferences in cis Natural Antisense Transcripts of Humans and Mice
    journal, April 2007


    Transcriptional interference by RNA polymerase pausing and dislodgement of transcription factors
    journal, January 2011

    • Palmer, Adam C.; Egan, J. Barry; Shearwin, Keith E.
    • Transcription, Vol. 2, Issue 1
    • DOI: 10.4161/trns.2.1.13511