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Title: The constrained architecture of mammalian Hox gene clusters

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America

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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC); European Research Council (ERC)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1560602
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, Issue 27; ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)Copyright Statement
Country of Publication:
United States
Language:
English

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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
The rise and fall of Hox gene clusters journal June 2007
A mutational analysis of the 5′ HoxD genes: dissection of genetic interactions during limb development in the mouse journal April 1996
Function of posterior HoxD genes in the morphogenesis of the anal sphincter journal September 1996
Ulnaless (Ul), a regulatory mutation inducing both loss-of-function and gain-of-function of posterior Hoxd genes journal September 1997
Distinct Roles and Regulations for Hoxd Genes in Metanephric Kidney Development journal January 2005
Transcriptional interference networks coordinate the expression of functionally related genes clustered in the same genomic loci journal January 2012
Transcriptional interference by RNA polymerase pausing and dislodgement of transcription factors journal January 2011

Figures / Tables (5)