Role of HOX genes and regula1on of gene expression Rob White - - PowerPoint PPT Presentation

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Nov 27, 2023 227 likes •462 views

Role of HOX genes and regula1on of gene expression Rob White Department of Physiology, Development and Neuroscience University of Cambridge Hox Mutants - Homeo1c phenotypes in Drosophila Wild type Loss of Ubx Hox gene func1on Wild type

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Role of HOX genes and regula1on of gene expression

Rob White

Department of Physiology, Development and Neuroscience University of Cambridge

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Wild type Wild type Loss of Ubx Hox gene func1on Ectopic mis-expression of Hox gene Antp

Hox Mutants - Homeo1c phenotypes in Drosophila

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Conserva1on of Hox genes and their expression

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Hox gene complexes

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Hox genes paGern the anterior-posterior axis

From Kosman et al (2004)

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Hox gene expression - a developmental code

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The Hox Code - paGerning the mammalian axial skeleton

McIntyre et al (2007) Development 134: 2981-2989

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Hox homeodomain DNA binding and Hox specificity

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Slattery et al (2011) Cell 147,1270-82

Hox cofactors

Drosophila Extraden1cle and Homothorax Vertebrate Pbx and Meis proteins

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Hox proteins binds to thousands of sites in the Drosophila genome Ubx Ubx + Exd/Hth

Sites in Genome: Ubx 8,672 Ubx + Exd/Hth 11,698

Beh et al (2016) Epigene1cs and Chroma1n 9:1

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Master regulators or Micromanagers?

Hox gene High level regulators Realisator genes Low level regulators Hox gene High level regulators Realisator genes Low level regulators

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Hox target genes

Choo et al (2011) PLoS ONE 6:e14778

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Hox genes control motor neuron iden1ty and circuits

Philippidou and Dasen (2013) Neuron 80; 12-34

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Zakany and Duboule (2007) Curr Op Gen and Dev 17:359-366

Hox genes are re-used in Proximal-Distal paGerning in vertebrate limbs

Pineault and Wellick (2014) Curr. Osteoporos Rep 12:420-427

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Hox genes micromanaging cell processes

Hox genes

Differen1a1on Cell shape Cell migra1on Cell prolifera1on Cell death Cell adhesion

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Allen and Taatjes (2015) Nature Reviews M C B 16, 155–166

Enhancer-Promoter Loops in Gene Regula1on

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Long-range Regulatory Elements

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Topologically-Associated Domains (TADs)

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Rao et al (2014) Cell 159: 1665-1680 Sanborn et al (2015) PNAS : E6456-6465

The domain organisa1on of the genome

TADs – Topologically Associated Domains

Dixon et al (2012) Nature 485: 376-380

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Lonfat and Duboule (2015) FEBSLeGs 589: 2869-2876

Domain organisa1on and HoxD regula1on

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Lupianez et al (2015) Cell 161:1012-1025

Enhancer range is delimited by domain boundaries

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Domain Structure : Polytene Chromosomes

Balbiani (1881)