Hox genes. Discovered in Drosophila in 1923 by Bridges and Morgan Antennapaedia complex ANT-C Bithorax complex BX-C

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1 Hox genes Establish body plan during development Specify head to tail axis of animal embryos Head Hox genes, abdomen hox genes. Mutations can cause one body part to transform to another 39 transcription factors genes organized in 4 clusters Four clusters called HOXA to HOXD Specify positional identity of cells

2 Hox genes Discovered in Drosophila in 1923 by Bridges and Morgan Antennapaedia complex ANT-C Bithorax complex BX-C

3 Hox genes

4 Hox genes show colinearity Colinearity - order of genes is same as the head-to-tail expression pattern!!! Temporal and spatial expression pattern is correlated to location in cluster! Mallo, M and Alonso, CR (2013). The regulation of Hox gene expression during animal development. Development 140:

5 Hox genes show colinearity This expression is maintained epigenetically. Mallo, M and Alonso, CR (2013). The regulation of Hox gene expression during animal development. Development 140:

6 This relationship is evolutionarily conserved vertebrates had 2 rounds of genome duplication

7 This relationship is evolutionarily conserved Lemons, D and McGinnis, W (2006). Genomic evolution of Hox gene clusters. Science 313:

8 This head to toe expression pattern is produced by regulation at many levels during gene expression. Expression is molded by transcription factors involved in earlier steps of development a memory system that uses Polycomb (PcG) and Trithorax (TrxG) group proteins regulation of one Hox gene by another micrornas lncrnas

9 Epigenetic regulation Transcriptional activation produced by transcription factors in early embryo are remembered through the action of Polycomb (PcG) and Trithorax (TrxG) group transcription factors.

10 Epigenetic regulation Trithorax group (TrxG) H3K4 HMTase produces H3K4me3 which maintains open chromatin Polycomb group (PcG) - two complexes belong here PRC1 and PRC2 PRC2 - H3K27 HMTase maintains closed chromatin PRC1 binds H3K27me3 and ubiquitylates H2A at K119 Montavon, T and Duboule, D (2013). Chromatin organization and global regulation of Hox gene clusters. Philos Trans R Soc

11 Representation of different aspects of Hox gene regulation associated with chromatin/nuclear characteristics. Mallo M, and Alonso C R Development 2013;140:

12 Vertebrates Embryonic Stem cells (a) (i) K27 K27 K27 K27 K27 K27 K27 K27 K27 K27 As the embryo develops H3K27me3 is removed and H3K4me3 appears. (ii) (iii) K27 demethylation, K4 methylation K27 K27 K27 K27 K4 K4 K4 K4 K4 K4 K27 demethylation, K4 methylation K4 K4 K4 K4 K4 K4 K4 K4 K4 K4 Montavon, T and Duboule, D (2013). Chromatin organization and global regulation of Hox gene clusters. Philos Trans R Soc Lond B Biol Sci 368:

13 Vertebrates Embryonic Stem cells (a) (i) Repression promotes movement and movement promotes repression (b) silent (i) K27 K27 K27 K27 K27 K27 K27 K27 K27 K27 anterior As the embryo develops H3K27me3 is removed and H3K4me3 appears. (ii) (iii) K27 demethylation, K4 methylation K27 K27 K27 K27 K4 K4 K4 K4 K4 K4 K27 demethylation, K4 methylation K4 K4 K4 K4 K4 K4 K4 K4 K4 K4 (ii) (iii) posterior Montavon, T and Duboule, D (2013). Chromatin organization and global regulation of Hox gene clusters. Philos Trans R Soc Lond B Biol Sci 368: ollinearity during trunk extension and chromatin dynamics at Hox clusters. Expression of Hox gene along the anterior-to-posterior (AP) em active

14 HOTAIR Frances R Goodman. Congenital abnormalities of body patterning: embryology revisited/ The Lancet, Volume 362, Issue 9384, Pages , 23 August 2003 Temporal lncrna transcribed from between HOXC11 and HOXC12 Blocks expression in posterior Hox D cluster recruits PRC2 and the LSD histone demethylation

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18 "#$%&'()*#* #$""-'%.4'/0$123.2'".5'*'"$ :N5*1(43(8.:N5*. Fatica, A and Bozzoni, I (2013). Long non-coding RNAs: #&""()!!+= new players in cell differentiation and development. Nat Rev Genet 8.:1G5*. +&,-. /%01 78,-1!$""()!*+, /%01 :+,='M$4%7H-M %7H-(!""!"#$%0"/#*.1'2./(!3, 8.:1G5*. 8.:;5*.