IRX1

IRX1 is a member of the Iroquois homeobox gene family. Members of this family play multiple roles during pattern formation in embryos of numerous vertebrate and invertebrate species.{{cite journal | vauthors = Kerner P, Ikmi A, Coen D, Vervoort M | title = Evolutionary history of the iroquois/Irx genes in metazoans | journal = BMC Evolutionary Biology | volume = 9 | issue = 74 | pages = 74 | date = April 2009 | pmid = 19368711 | pmc = 2674049 | doi = 10.1186/1471-2148-9-74 | doi-access = free | bibcode = 2009BMCEE...9...74K }} IRO genes are thought to function early in development to define large territories, and again later in development for further patterning specification. Experimental data suggest roles for IRX1 in vertebrates may include development and patterning of lungs, limbs, heart, eyes, and nervous system.{{cite journal | vauthors = Choy SW, Cheng CW, Lee ST, Li VW, Hui MN, Hui CC, Liu D, Cheng SH | title = A cascade of irx1a and irx2a controls shh expression during retinogenesis | journal = Developmental Dynamics | volume = 239 | issue = 12 | pages = 3204–3214 | date = December 2010 | pmid = 21046643 | doi = 10.1002/dvdy.22462 | s2cid = 38099649 | doi-access = free }}{{cite journal | vauthors = Cheng CW, Yan CH, Choy SW, Hui MN, Hui CC, Cheng SH | title = Zebrafish homologue irx1a is required for the differentiation of serotonergic neurons | journal = Developmental Dynamics | volume = 236 | issue = 9 | pages = 2661–2667 | date = September 2007 | pmid = 17685478 | doi = 10.1002/dvdy.21272 | s2cid = 142831 | doi-access = free }}{{cite journal | vauthors = Becker MB, Zülch A, Bosse A, Gruss P | title = Irx1 and Irx2 expression in early lung development | journal = Mechanisms of Development | volume = 106 | issue = 1–2 | pages = 155–158 | date = August 2001 | pmid = 11472847 | doi = 10.1016/S0925-4773(01)00412-9 | s2cid = 16857354 | doi-access = }}{{cite journal | vauthors = Bosse A, Zülch A, Becker MB, Torres M, Gómez-Skarmeta JL, Modolell J, Gruss P | title = Identification of the vertebrate Iroquois homeobox gene family with overlapping expression during early development of the nervous system | journal = Mechanisms of Development | volume = 69 | issue = 1–2 | pages = 169–181 | date = December 1997 | pmid = 9486539 | doi = 10.1016/S0925-4773(97)00165-2 | hdl-access = free | s2cid = 9655500 | hdl = 11858/00-001M-0000-0012-FE9F-5 }}{{cite journal | vauthors = Christoffels VM, Keijser AG, Houweling AC, Clout DE, Moorman AF | title = Patterning the embryonic heart: identification of five mouse Iroquois homeobox genes in the developing heart | journal = Developmental Biology | volume = 224 | issue = 2 | pages = 263–274 | date = August 2000 | pmid = 10926765 | doi = 10.1006/dbio.2000.9801 | doi-access = free }}{{cite journal | vauthors = Díaz-Hernández ME, Bustamante M, Galván-Hernández CI, Chimal-Monroy J | title = Irx1 and Irx2 are coordinately expressed and regulated by retinoic acid, TGFβ and FGF signaling during chick hindlimb development | journal = PLOS ONE | volume = 8 | issue = 3 | pages = e58549 | date = March 11, 2013 | pmid = 23505533 | pmc = 3594311 | doi = 10.1371/journal.pone.0058549 | bibcode = 2013PLoSO...858549D | doi-access = free }}

IRX1 is located on the forward DNA strand (see Sense (molecular biology)) of chromosome 5, from position 3596054 - 3601403 at the 5p15.3 location. The human gene product is a 1858 base pair mRNA with 4 predicted exons in humans.{{Cite web |title=NCBI Nucleotide: IRX1 |url=https://www.ncbi.nlm.nih.gov/nuccore/NM_024337.3 |access-date=May 17, 2014}} Promoter analysis was performed using El Dorado through the Genomatix software page.{{Cite web |title=El Dorado |url=http://www.genomatix.de/cgi-bin/eldorado/main.pl |access-date=May 17, 2014 |publisher=Genomatix }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }} The predicted promoter region spans 1040 base pairs from position 3595468 through 3595468 on the forward strand of chromosome 5.

IRX1 is relatively isolated, with no other protein coding genes found from position 3177835 – 5070004.

Microarray and RNA seq data suggest that IRX1 is ubiquitously expressed at low levels in adult tissues, with the highest relative levels of expression occurring in the heart, adipose, kidney, and breast tissues.{{Cite web |title=BioGPS: IRX1 |url=http://biogps.org/#goto=genereport&id=79192 |access-date=17 May 2014}}{{Cite web |title=GeneCards: IRX1 |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=IRX1&search=irx1 |access-date=17 May 2014}} Moderate to high levels are also indicated in the lung, prostate and stomach.{{Cite web |title=GEO Profile: IRX1 |url=https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS3834:8760 |access-date=May 17, 2014}} Promoter analysis with the El Dorado program from Genomatix predicted that IRX1 expression is regulated by factors that include E2F cell cycle regulators, NRF1, and ZF5,{{cite journal | vauthors = Numoto M, Yokoro K, Koshi J | title = ZF5, which is a Kruppel-type transcriptional repressor, requires the zinc finger domain for self-association | journal = Biochemical and Biophysical Research Communications | volume = 256 | issue = 3 | pages = 573–578 | date = March 1999 | pmid = 10080939 | doi = 10.1006/bbrc.1999.0375 }} and brachyury. Expression data from human, mouse, and developing mouse brains are available though the Allen Brain Atlas.{{Cite web |title=Allen Brain Atlas |url=http://www.brain-map.org/ |access-date=May 17, 2014}}

The mature IRX1 protein has 480 amino acid residues, with a molecular mass of 49,600 daltons and an isoelectric point of 5.7. A BLAST search revealed that IRX1 contains two highly conserved domains: a homeodomain and a characteristic IRO motif of unknown function.{{Cite web |title=IRX1 Analysis |url=http://seqtool.sdsc.edu/CGI/BW.cgi |access-date=8 May 2014 |website=Biology Workbench |publisher=San Diego Supercomputing Center- University of California San Diego}}{{dead link|date=November 2017 |bot=InternetArchiveBot |fix-attempted=yes }} The homeodomain belongs to the TALE (three amino acid loop extension) class of homeodomains, and is characterized by the addition of three extra amino acids between the first and second helix of three alpha helices that comprise the domain.{{cite journal | vauthors = Bürglin TR | title = Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals | journal = Nucleic Acids Research | volume = 25 | issue = 21 | pages = 4173–4180 | date = November 1997 | pmid = 9336443 | pmc = 147054 | doi = 10.1093/nar/25.21.4173 }} The presence of this well characterized homeodomain strongly suggests that IRX1 acts as a transcription factor. This is further supported by the predicted localization of IRX1 to the nucleus.{{Cite web |title=Expasy: Psort |url=http://psort.hgc.jp/cgi-bin/runpsort.pl |access-date=18 May 2014}}{{dead link|date=April 2017 |bot=InternetArchiveBot |fix-attempted=yes }} The IRO motif is a region downstream of the homeodomain that is found only in members of the Iroquois-class homeodomain proteins, though its function is poorly understood. However, its similarity to an internal region of the Notch receptor protein suggests that it may be involved with protein-protein interaction. In addition to these two characteristic domains, IRX1 contains a third domain from the HARE-HTH superfamily{{cite journal | vauthors = Aravind L, Iyer LM | title = The HARE-HTH and associated domains: novel modules in the coordination of epigenetic DNA and protein modifications | journal = Cell Cycle | volume = 11 | issue = 1 | pages = 119–131 | date = January 2012 | pmid = 22186017 | pmc = 3272235 | doi = 10.4161/cc.11.1.18475 }} fused to the C-terminal end of the homeodomain.{{Cite web |title=NCBI Protein: IRX1 |url=https://www.ncbi.nlm.nih.gov/protein/51479177 |access-date=18 May 2014}} This domain adopts a winged helix-turn-helix fold predicted to bind DNA, and is thought to play a role in recruiting effector activities to DNA. Several forms of post-translational modification are predicted, including SUMOylation, C-mannosylation, and phosphorylation, using bioinformatics tools from ExPASy.{{Cite web |title=ExPASy: Bioinformatics Resource Portal |url=http://expasy.org/ |access-date=18 May 2014}} Bioinformatic analysis of IRX1 with the NetPhos tool predicted 71 potential phosphorylation sites throughout the protein.{{Cite web |title=NetPhos |url=http://www.cbs.dtu.dk/services/NetPhos/ |access-date=18 May 2014}}

Potential protein interacting partners for IRX1 were found using computational tools. The STRING database lists nine putative interacting partners supported by text mining evidence, though closer analysis of the results shows little support for most of these predicted interactions.{{Cite web |title=STRING Database |url=http://string-db.org/newstring_cgi/show_network_section.pl |access-date=5 May 2014}} However, it is possible that one of these proteins, CDKN1A, is involved in the predicted regulation of IRX1 by E2F cell cycle regulators.

IRX1 has a high degree of conservation across vertebrate and invertebrate species. The entire protein is more fully conserved through vertebrate species, while only the homeodomain and IRO motif are conserved in more distant homologs.

Homologous sequences were found in species as distantly related to humans as the pig roundworm Ascaris suum, from the family Ascarididae, using BLAST and the ALIGN tool through the San Diego Super Computer Biology Workbench. The following is a table describing the evolutionary conservation of IRX1.

IRX1 is one of six members of the Iroquois-class homeodomain proteins found in humans: IRX2, IRX3, IRX4, IRX5, and IRX6. IRX1, IRX2, and IRX4 are found on human chromosome 5, and their orientation corresponds to that of IRX3, IRX5, and IRX6 found on human chromosome 16. It is thought that the genomic organization of IRO genes in conserved gene clusters allows for coregulation and enhancer sharing during development.

{{reflist|35em}}

{{refbegin|35em}}

• {{cite journal | vauthors = Lam CY, Tam PO, Fan DS, Fan BJ, Wang DY, Lee CW, Pang CP, Lam DS | title = A genome-wide scan maps a novel high myopia locus to 5p15 | journal = Investigative Ophthalmology & Visual Science | volume = 49 | issue = 9 | pages = 3768–3778 | date = September 2008 | pmid = 18421076 | doi = 10.1167/iovs.07-1126 | doi-access = }}
• {{cite journal | vauthors = Cirulli ET, Kasperaviciūte D, Attix DK, Need AC, Ge D, Gibson G, Goldstein DB | title = Common genetic variation and performance on standardized cognitive tests | journal = European Journal of Human Genetics | volume = 18 | issue = 7 | pages = 815–820 | date = July 2010 | pmid = 20125193 | pmc = 2987367 | doi = 10.1038/ejhg.2010.2 }}
• {{cite journal | vauthors = Trynka G, Zhernakova A, Romanos J, Franke L, Hunt KA, Turner G, Bruinenberg M, Heap GA, Platteel M, Ryan AW, de Kovel C, Holmes GK, Howdle PD, Walters JR, Sanders DS, Mulder CJ, Mearin ML, Verbeek WH, Trimble V, Stevens FM, Kelleher D, Barisani D, Bardella MT, McManus R, van Heel DA, Wijmenga C | title = Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling | journal = Gut | volume = 58 | issue = 8 | pages = 1078–1083 | date = August 2009 | pmid = 19240061 | doi = 10.1136/gut.2008.169052 | s2cid = 17111427 }}
• {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 | doi-access = free }}
• {{cite journal | vauthors = Lewis MT, Ross S, Strickland PA, Snyder CJ, Daniel CW | title = Regulated expression patterns of IRX-2, an Iroquois-class homeobox gene, in the human breast | journal = Cell and Tissue Research | volume = 296 | issue = 3 | pages = 549–554 | date = June 1999 | pmid = 10370142 | doi = 10.1007/s004410051316 | s2cid = 37046813 }}
• {{cite journal | vauthors = Bennett KL, Karpenko M, Lin MT, Claus R, Arab K, Dyckhoff G, Plinkert P, Herpel E, Smiraglia D, Plass C | title = Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma | journal = Cancer Research | volume = 68 | issue = 12 | pages = 4494–4499 | date = June 2008 | pmid = 18559491 | doi = 10.1158/0008-5472.CAN-07-6509 | doi-access = free }}

{{refend}}

{{NLM content}}

{{Transcription factors|g3}}

Category:Transcription factors