Editing Homeobox (section)

===Hox genes===
[[File:Hoxgenesoffruitfly.svg|Hox gene expression in ''Drosophila melanogaster''.|thumb|right|400px]]
{{Main|Hox gene}}

Hox genes are the most commonly known subset of homeobox genes. They are essential [[Metazoa|metazoan]] genes that determine the identity of embryonic regions along the anterior-posterior axis.<ref name="pmid124454032">{{cite journal | vauthors = Alonso CR | title = Hox proteins: sculpting body parts by activating localized cell death | journal = Current Biology | volume = 12 | issue = 22 | pages = R776-8 | date = November 2002 | pmid = 12445403 | doi = 10.1016/S0960-9822(02)01291-5 | s2cid = 17558233 | doi-access = free | bibcode = 2002CBio...12.R776A }}</ref>  The first vertebrate Hox gene was isolated in ''[[Xenopus]]'' by [[Edward M. De Robertis|Edward De Robertis]] and colleagues in 1984.<ref name="pmid63270662">{{cite journal | vauthors = Carrasco AE, McGinnis W, Gehring WJ, De Robertis EM | title = Cloning of an X. laevis gene expressed during early embryogenesis coding for a peptide region homologous to Drosophila homeotic genes | journal = Cell | volume = 37 | issue = 2 | pages = 409–14 | date = June 1984 | pmid = 6327066 | doi = 10.1016/0092-8674(84)90371-4 | s2cid = 30114443 }}</ref> The main interest in this set of genes stems from their unique behavior and arrangement in the genome. Hox genes are typically found in an organized cluster. The linear order of Hox genes within a cluster is directly correlated to the order in which they are expressed in both time and space during development. This phenomenon is called colinearity. 

Mutations in these [[Homeotic gene|homeotic genes]] cause displacement of body segments during embryonic development. This is called [[Ectopic expression|ectopia]]. For example, when one gene is lost the segment develops into a more anterior one, while a mutation that leads to a gain of function causes a segment to develop into a more posterior one. Famous examples are ''[[Antennapedia]]'' and [[Bithorax complex|bithorax]] in ''Drosophila'', which can cause the development of legs instead of antennae and the development of a duplicated thorax, respectively.<ref>{{cite journal | vauthors = Schneuwly S, Klemenz R, Gehring WJ | title = Redesigning the body plan of Drosophila by ectopic expression of the homoeotic gene Antennapedia | journal = Nature | volume = 325 | issue = 6107 | pages = 816–8 | date = 1987 | pmid = 3821869 | doi = 10.1038/325816a0 | bibcode = 1987Natur.325..816S | s2cid = 4320668 }}</ref>

In vertebrates, the four [[Homology (biology)|paralog]] clusters are partially redundant in function, but have also acquired several derived functions. For example, HoxA and HoxD specify segment identity along the [[Limb (anatomy)|limb]] axis.<ref>{{cite journal | vauthors = Fromental-Ramain C, Warot X, Messadecq N, LeMeur M, Dollé P, Chambon P | title = Hoxa-13 and Hoxd-13 play a crucial role in the patterning of the limb autopod | journal = Development | volume = 122 | issue = 10 | pages = 2997–3011 | date = October 1996 | doi = 10.1242/dev.122.10.2997 | pmid = 8898214 }}</ref><ref>{{cite journal | vauthors = Zákány J, Duboule D | title = Hox genes in digit development and evolution | journal = Cell and Tissue Research | volume = 296 | issue = 1 | pages = 19–25 | date = April 1999 | pmid = 10199961 | doi = 10.1007/s004410051262 | s2cid = 3192774 }}</ref> Specific members of the Hox family have been implicated in vascular remodeling, [[angiogenesis]], and disease by orchestrating changes in matrix degradation, integrins, and components of the ECM.<ref>{{cite journal | vauthors = Gorski DH, Walsh K | title = The role of homeobox genes in vascular remodeling and angiogenesis | journal = Circulation Research | volume = 87 | issue = 10 | pages = 865–72 | date = November 2000 | pmid = 11073881 | doi = 10.1161/01.res.87.10.865 | doi-access = free }}</ref> HoxA5 is implicated in atherosclerosis.<ref name="ReferenceA2">{{cite journal | vauthors = Dunn J, Thabet S, Jo H | title = Flow-Dependent Epigenetic DNA Methylation in Endothelial Gene Expression and Atherosclerosis | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 35 | issue = 7 | pages = 1562–9 | date = July 2015 | pmid = 25953647 | pmc = 4754957 | doi = 10.1161/ATVBAHA.115.305042 }}</ref><ref>{{cite journal | vauthors = Dunn J, Simmons R, Thabet S, Jo H | title = The role of epigenetics in the endothelial cell shear stress response and atherosclerosis | journal = The International Journal of Biochemistry & Cell Biology | volume = 67 | pages = 167–76 | date = October 2015 | pmid = 25979369 | pmc = 4592147 | doi = 10.1016/j.biocel.2015.05.001 }}</ref> HoxD3 and HoxB3 are proinvasive, angiogenic genes that upregulate b3 and a5 integrins and Efna1 in ECs, respectively.<ref>{{cite journal | vauthors = Boudreau N, Andrews C, Srebrow A, Ravanpay A, Cheresh DA | title = Induction of the angiogenic phenotype by Hox D3 | journal = The Journal of Cell Biology | volume = 139 | issue = 1 | pages = 257–64 | date = October 1997 | pmid = 9314544 | pmc = 2139816 | doi = 10.1083/jcb.139.1.257 }}</ref><ref>{{cite journal | vauthors = Boudreau NJ, Varner JA | title = The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis | journal = The Journal of Biological Chemistry | volume = 279 | issue = 6 | pages = 4862–8 | date = February 2004 | pmid = 14610084 | doi = 10.1074/jbc.M305190200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Myers C, Charboneau A, Boudreau N | title = Homeobox B3 promotes capillary morphogenesis and angiogenesis | journal = The Journal of Cell Biology | volume = 148 | issue = 2 | pages = 343–51 | date = January 2000 | pmid = 10648567 | pmc = 2174277 | doi = 10.1083/jcb.148.2.343 }}</ref><ref>{{cite journal | vauthors = Chen Y, Xu B, Arderiu G, Hashimoto T, Young WL, Boudreau N, Yang GY | title = Retroviral delivery of homeobox D3 gene induces cerebral angiogenesis in mice | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 24 | issue = 11 | pages = 1280–7 | date = November 2004 | pmid = 15545924 | doi = 10.1097/01.WCB.0000141770.09022.AB | doi-access = free }}</ref> HoxA3 induces [[endothelial]] cell (EC) migration by upregulating MMP14 and uPAR. Conversely, HoxD10 and HoxA5 have the opposite effect of suppressing EC migration and angiogenesis, and stabilizing adherens junctions by upregulating TIMP1/downregulating uPAR and MMP14, and by upregulating Tsp2/downregulating VEGFR2, Efna1, Hif1alpha and COX-2, respectively.<ref>{{cite journal | vauthors = Myers C, Charboneau A, Cheung I, Hanks D, Boudreau N | title = Sustained expression of homeobox D10 inhibits angiogenesis | journal = The American Journal of Pathology | volume = 161 | issue = 6 | pages = 2099–109 | date = December 2002 | pmid = 12466126 | pmc = 1850921 | doi = 10.1016/S0002-9440(10)64488-4 }}</ref><ref>{{cite journal | vauthors = Mace KA, Hansen SL, Myers C, Young DM, Boudreau N | title = HOXA3 induces cell migration in endothelial and epithelial cells promoting angiogenesis and wound repair | journal = Journal of Cell Science | volume = 118 | issue = Pt 12 | pages = 2567–77 | date = June 2005 | pmid = 15914537 | doi = 10.1242/jcs.02399 | doi-access = free }}</ref> HoxA5 also upregulates the tumor suppressor p53 and Akt1 by downregulation of PTEN.<ref>{{cite journal | vauthors = Rhoads K, Arderiu G, Charboneau A, Hansen SL, Hoffman W, Boudreau N | title = A role for Hox A5 in regulating angiogenesis and vascular patterning | journal = Lymphatic Research and Biology | volume = 3 | issue = 4 | pages = 240–52 | year = 2005 | pmid = 16379594 | doi = 10.1089/lrb.2005.3.240 }}</ref> Suppression of HoxA5 has been shown to attenuate [[hemangioma]] growth.<ref name="Arderiu, G. 20072">{{cite journal | vauthors = Arderiu G, Cuevas I, Chen A, Carrio M, East L, Boudreau NJ | title = HoxA5 stabilizes adherens junctions via increased Akt1 | journal = Cell Adhesion & Migration | volume = 1 | issue = 4 | pages = 185–95 | year = 2007 | pmid = 19262140 | pmc = 2634105 | doi = 10.4161/cam.1.4.5448 }}</ref> HoxA5 has far-reaching effects on gene expression, causing ~300 genes to become upregulated upon its induction in breast cancer cell lines.<ref name="Arderiu, G. 20072" /> HoxA5 protein transduction domain overexpression prevents inflammation shown by inhibition of TNFalpha-inducible monocyte binding to HUVECs.<ref>{{cite journal | vauthors = Zhu Y, Cuevas IC, Gabriel RA, Su H, Nishimura S, Gao P, Fields A, Hao Q, Young WL, Yang GY, Boudreau NJ | title = Restoring transcription factor HoxA5 expression inhibits the growth of experimental hemangiomas in the brain | journal = Journal of Neuropathology and Experimental Neurology | volume = 68 | issue = 6 | pages = 626–32 | date = June 2009 | pmid = 19458547 | pmc = 2728585 | doi = 10.1097/NEN.0b013e3181a491ce }}</ref><ref>{{cite journal | vauthors = Chen H, Rubin E, Zhang H, Chung S, Jie CC, Garrett E, Biswal S, Sukumar S | title = Identification of transcriptional targets of HOXA5 | journal = The Journal of Biological Chemistry | volume = 280 | issue = 19 | pages = 19373–80 | date = May 2005 | pmid = 15757903 | doi = 10.1074/jbc.M413528200 | doi-access = free }}</ref>