DACH1

Dachshund homolog 1, also known as DACH1, is a protein which in humans is encoded by the DACH1 gene.[5][6][7] DACH1 has been shown to interact with Ubc9,[8] Smad4,[9] and NCoR.[9][10]

DACH1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1L8R
Identifiers
Aliases	DACH1, DACH, dachshund family transcription factor 1
External IDs	OMIM: 603803 MGI: 1277991 HomoloGene: 7288 GeneCards: DACH1
Gene location (Human) Chr. Chromosome 13 (human)[1] Band 13q21.33 Start 71,437,966 bp[1] End 71,867,204 bp[1]
Gene location (Mouse) Chr. Chromosome 14 (mouse)[2] Band 14 E2.1|14 48.25 cM Start 97,786,853 bp[2] End 98,169,765 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • DNA binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • GO:0001078, GO:0001214, GO:0001206 DNA-binding transcription repressor activity, RNA polymerase II-specific • GO:0001948 protein binding • RNA polymerase II regulatory region sequence-specific DNA binding • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • GO:0000983 RNA polymerase II general transcription initiation factor activity • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component • cytoplasm • cell nucleus • transcription factor complex Biological process • regulation of transcription, DNA-templated • negative regulation of transcription by competitive promoter binding • RNA polymerase II transcriptional preinitiation complex assembly • negative regulation of transcription from RNA polymerase II promoter • respiratory gaseous exchange • transcription, DNA-templated • development of primary female sexual characteristics • negative regulation of cell migration • regulation of nuclear cell cycle DNA replication • negative regulation of cell proliferation involved in contact inhibition • cellular proliferation • negative regulation of transcription, DNA-templated • negative regulation of fibroblast proliferation • negative regulation of DNA biosynthetic process • suckling behavior • multicellular organism development • transcription from RNA polymerase II promoter Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1602	13134
Ensembl	ENSG00000276644	ENSMUSG00000055639
UniProt	Q9UI36	Q9QYB2
RefSeq (mRNA)	NM_004392 NM_080759 NM_080760 NM_001366712	NM_001038610 NM_007826
RefSeq (protein)	NP_004383 NP_542937 NP_542938 NP_001353641	NP_001033699 NP_031852
Location (UCSC)	Chr 13: 71.44 – 71.87 Mb	Chr 14: 97.79 – 98.17 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Gene structure . This protein coding gene has 760 amino acid protein, and an observed molecular weight of 52 kDa. Dachshund Family transcription factor 1 is encoded by DACH gene, who spans 400kDa and is encoded by 12 exons. This gene is located, in humans, in chromosome 13 (13q22). It encodes a chromatin-associated protein that associates with other DNA-binding transcription factors to regulate gene expression,[9][11][12][10][13][14] mRNA translation,[15] coactivator binding,[16] and cell fate determination during development.[17][18]

Multiple transcript variants encoding different isoforms have been found for this gene. Four alternatively spliced transcripts encoding different isoforms have been described for this gene.DACH1 mRNA was detected in multiple human tissues, including kidney and heart. Dach1 is located in nuclear and cytoplasmic pools and is considered a cell fate determination factor.[17][18] Dachshund domain 1 (DD1, also known as Box-N) has a predicted helix–turn–helix family structure. The X-ray crystal structure of the human DACH1 Box-N illustrates that the DACH1 protein contains a domain that is conserved with the pro-oncogenes ski/sno oncogenes, which form an α/β structure similar to that found in the winged helix/forkhead subgroup of DNA binding proteins.[14] This protein is widely expressed including bone marrow, brain, colon, eye, heart, kidney, leucocyte, liver, lung, pancreas, pineal gland, placenta, prostate, retina, skeletal muscle, small intestine, stromal/preosteoblasts and the spleen.[10][19][20]

Protein modification. DACH1 is modified by phosphorylation,[15] acetylation,[21] and SUMOYlation.[22] Acetylation of Dach1 determine binding to the p53 tumor suppressor, and thereby governs a subset of p53 functions involved in stem cell restraint and the inhibition of cellular proliferation.[21] SUMOYlation of DACH governs HDAC binding.[23] Phosphorylation of Dach1 contributes to YB-1 binding, subcellular distribution and the induction of EMT via translation of EMT regulatory genes.[15]

DACH1 Secondary Structure.[24]

Function

Organismal development. Dach1 is similar to the D. melanogaster dac gene, which encodes a nuclear factor essential for determining cell fates in the eye, leg, and nervous system of the fly.[6] Dach is a member of the Ski gene family and is involved in eye and organismal development.[18][25] Dach1 deletion mice exhibit early postnatal death, although no developmental defects were detected in any organ system examined, including kidneys. DACH1 plays an important role on this precursor of cell proliferation in retinal and pituitary.[7][17][26]

Restrain of Cancer cell growth. DACH1 protein is able to prevent the proliferation of cancerous cells (lung, breast, prostate[11][12][10][13][14]) and functions as a repressor of estrogen receptor activity in breast cancer cells.[11][13]

Transcription. DACH1 conducts transcriptional function through interacting with transcription factors including c-Jun,[11] estrogen receptor alpha,[13] the androgen receptor,[10] and the basal transcription apparatus through binding to the co-integrator protein CA150. Curiously, DACH1 selectively bound to the delta domain of c-Jun, which was known to interact with an endogenous cellular repressor. DACH1 binds directly with a Forkhead-like DNA sequence to restrain oncogenic signals from a subset of FKHR proteins.[14] Dach1 governs mRNA translation of an EMT signature[15] and governs Snail1 transcription.[15]

Cell migration. DACH1 inhibits migration of vascular endothelial cells,[23][27] fibroblasts[28] and prostate epithelial cells[27] wherein DACH1 maintains persistence of migratory directionality via heterotypic signals.

Disease relevance

Cancer

DACH1 has been implicated in suppression of tumor growth, and has been proposed as a putatative tumor suppressor although no formal in vivo evidence has been published to date. Supporting evidence includes the finding that Dach1 expression is reduced in human malignancies including breast,[26][15] lung,[12] prostate[10] and brain tumors.[29] DACH1 inhibits Cyclin D1 expression and thereby reduces breast cancer cell line cell growth.[28] Normal cells and some breast cancer cells have receptors that bind estrogen and progesterone. These two hormones often promote the growth of breast cancer cells. Approximately 70% of breast cancers are ERa+, DACH1 expression decreases when the cancer is more invasive and the level of estrogen is high.[13]

Nephropathy

Renal hypodysplasia (RHD) is characterized by small and/or disorganized kidneys following abnormal organogenesis. Double homozygous missense mutations of DACH1 and BMP4 occurred in a patient with bilateral cystic dysplasia.[30] Functional analysis of the DACH1 mutation (p.R684C). demonstrated enhanced suppression of the TGF-β pathway. Dach1 is highly expressed in the adult podocyte, with transcripts showing an approximate tenfold enrichment compared to total kidney cortex. It is also more widely expressed in the earlier developing kidney, but again including definite podocyte expression.

Diabetes

Hepatocyte the abundance of DACH1 Is Increased in the hepatocytes of Obese patients. Dach1 promotes hepatic insulin resistance via Nuclear Exclusion of HDAC4.[23]

References

1. GRCh38: Ensembl release 89: ENSG00000276644 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000055639 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Gene: DACH1 (ENSG00000276644) - Summary - Homo sapiens - Ensembl genome browser 89". may2017.archive.ensembl.org. Retrieved 2017-09-28.
6. Mardon G, Solomon NM, Rubin GM (December 1994). "dachshund encodes a nuclear protein required for normal eye and leg development in Drosophila". Development. 120 (12): 3473–86. PMID 7821215.
7. Shen W, Mardon G (January 1997). "Ectopic eye development in Drosophila induced by directed dachshund expression". Development. 124 (1): 45–52. PMID 9006066.
8. Machon O, Backman M, Julin K, Krauss S (October 2000). "Yeast two-hybrid system identifies the ubiquitin-conjugating enzyme mUbc9 as a potential partner of mouse Dac". Mechanisms of Development. 97 (1–2): 3–12. doi:10.1016/s0925-4773(00)00402-0. PMID 11025202.
9. Wu K, Yang Y, Wang C, Davoli MA, D'Amico M, Li A, Cveklova K, Kozmik Z, Lisanti MP, Russell RG, Cvekl A, Pestell RG (December 2003). "DACH1 inhibits transforming growth factor-beta signaling through binding Smad4". The Journal of Biological Chemistry. 278 (51): 51673–84. doi:10.1074/jbc.M310021200. PMID 14525983.
10. Wu K, Katiyar S, Witkiewicz A, Li A, McCue P, Song LN, Tian L, Jin M, Pestell RG (April 2009). "The cell fate determination factor dachshund inhibits androgen receptor signaling and prostate cancer cellular growth". Cancer Research. 69 (8): 3347–55. doi:10.1158/0008-5472.CAN-08-3821. PMC 2669850. PMID 19351840.
11. Wu K, Liu M, Li A, Donninger H, Rao M, Jiao X, Lisanti MP, Cvekl A, Birrer M, Pestell RG (March 2007). "Cell fate determination factor DACH1 inhibits c-Jun-induced contact-independent growth". Molecular Biology of the Cell. 18 (3): 755–67. doi:10.1091/mbc.E06-09-0793. PMC 1805093. PMID 17182846.
12. Chen K, Wu K, Cai S, Zhang W, Zhou J, Wang J, Ertel A, Li Z, Rui H, Quong A, Lisanti MP, Tozeren A, Tanes C, Addya S, Gormley M, Wang C, McMahon SB, Pestell RG (June 2013). "Dachshund binds p53 to block the growth of lung adenocarcinoma cells". Cancer Research. 73 (11): 3262–74. doi:10.1158/0008-5472.CAN-12-3191. PMC 3674204. PMID 23492369.
13. Popov VM, Zhou J, Shirley LA, Quong J, Yeow WS, Wright JA, Wu K, Rui H, Vadlamudi RK, Jiang J, Kumar R, Wang C, Pestell RG (July 2009). "The cell fate determination factor DACH1 is expressed in estrogen receptor-alpha-positive breast cancer and represses estrogen receptor-alpha signaling". Cancer Research. 69 (14): 5752–60. doi:10.1158/0008-5472.CAN-08-3992. PMC 3244171. PMID 19605405.
14. Zhou J, Wang C, Wang Z, Dampier W, Wu K, Casimiro MC, Chepelev I, Popov VM, Quong A, Tozeren A, Zhao K, Lisanti MP, Pestell RG (April 2010). "Attenuation of Forkhead signaling by the retinal determination factor DACH1". Proceedings of the National Academy of Sciences of the United States of America. 107 (15): 6864–9. doi:10.1073/pnas.1002746107. PMC 2872468. PMID 20351289.
15. Wu K, Chen K, Wang C, Jiao X, Wang L, Zhou J, Wang J, Li Z, Addya S, Sorensen PH, Lisanti MP, Quong A, Ertel A, Pestell RG (February 2014). "Cell fate factor DACH1 represses YB-1-mediated oncogenic transcription and translation". Cancer Research. 74 (3): 829–39. doi:10.1158/0008-5472.CAN-13-2466. PMC 3933065. PMID 24335958.
16. Zhou J, Liu Y, Zhang W, Popov VM, Wang M, Pattabiraman N, Suñé C, Cvekl A, Wu K, Jiang J, Wang C, Pestell RG (December 2010). "Transcription elongation regulator 1 is a co-integrator of the cell fate determination factor Dachshund homolog 1". The Journal of Biological Chemistry. 285 (51): 40342–50. doi:10.1074/jbc.M110.156141. PMC 3001014. PMID 20956529.
17. Davis TL, Rebay I (January 2017). "Master regulators in development: Views from the Drosophila retinal determination and mammalian pluripotency gene networks". Developmental Biology. 421 (2): 93–107. doi:10.1016/j.ydbio.2016.12.005. PMC 5496713. PMID 27979656.
18. Popov VM, Wu K, Zhou J, Powell MJ, Mardon G, Wang C, Pestell RG (January 2010). "The Dachshund gene in development and hormone-responsive tumorigenesis". Trends in Endocrinology and Metabolism. 21 (1): 41–9. doi:10.1016/j.tem.2009.08.002. PMC 2818438. PMID 19896866.
19. Sundaram K, Mani SK, Kitatani K, Wu K, Pestell RG, Reddy SV (April 2008). "DACH1 negatively regulates the human RANK ligand gene expression in stromal/preosteoblast cells". Journal of Cellular Biochemistry. 103 (6): 1747–59. doi:10.1002/jcb.21561. PMC 2778848. PMID 17891780.
20. Hammond KL, Lettice LA, Hill RE, Lee M, Boyle S, Hanson IM (January 1999). "Human (DACH) and mouse (Dach) homologues of Drosophila dachshund map to chromosomes 13q22 and 14E3, respectively". Genomics. 55 (2): 252–3. doi:10.1006/geno.1998.5662. PMID 9933575.
21. Chen K, Wu K, Gormley M, Ertel A, Wang J, Zhang W, Zhou J, Disante G, Li Z, Rui H, Quong AA, McMahon SB, Deng H, Lisanti MP, Wang C, Pestell RG (June 2013). "Acetylation of the cell-fate factor dachshund determines p53 binding and signaling modules in breast cancer". Oncotarget. 4 (6): 923–35. doi:10.18632/oncotarget.1094. PMC 3757249. PMID 23798621.
22. Ozcan L, Ghorpade DS, Zheng Z, de Souza JC, Chen K, Bessler M, Bagloo M, Schrope B, Pestell R, Tabas I (June 2016). "Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance". Cell Reports. 15 (10): 2214–2225. doi:10.1016/j.celrep.2016.05.006. PMC 5068925. PMID 27239042.
23. Chang AH, Raftrey BC, D'Amato G, Surya VN, Poduri A, Chen HI, Goldstone AB, Woo J, Fuller GG, Dunn AR, Red-Horse K (August 2017). "DACH1 stimulates shear stress-guided endothelial cell migration and coronary artery growth through the CXCL12-CXCR4 signaling axis". Genes & Development. 31 (13): 1308–1324. doi:10.1101/gad.301549.117. PMC 5580653. PMID 28779009.
24. "DACH1 - Dachshund homolog 1 - Homo sapiens (Human) - DACH1 gene & protein". www.uniprot.org. Retrieved 2016-10-22.
25. Wu K, Li A, Rao M, Liu M, Dailey V, Yang Y, Di Vizio D, Wang C, Lisanti MP, Sauter G, Russell RG, Cvekl A, Pestell RG (October 2006). "DACH1 is a cell fate determination factor that inhibits cyclin D1 and breast tumor growth". Molecular and Cellular Biology. 26 (19): 7116–29. doi:10.1128/MCB.00268-06. PMC 1592900. PMID 16980615.
26. Li X, Perissi V, Liu F, Rose DW, Rosenfeld MG (August 2002). "Tissue-specific regulation of retinal and pituitary precursor cell proliferation". Science. 297 (5584): 1180–3. doi:10.1126/science.1073263. PMID 12130660.
27. Chen K, Wu K, Jiao X, Wang L, Ju X, Wang M, Di Sante G, Xu S, Wang Q, Li K, Sun X, Xu C, Li Z, Casimiro MC, Ertel A, Addya S, McCue PA, Lisanti MP, Wang C, Davis RJ, Mardon G, Pestell RG (May 2015). "The endogenous cell-fate factor dachshund restrains prostate epithelial cell migration via repression of cytokine secretion via a cxcl signaling module". Cancer Research. 75 (10): 1992–2004. doi:10.1158/0008-5472.CAN-14-0611. PMC 4433595. PMID 25769723.
28. Wu K, Katiyar S, Li A, Liu M, Ju X, Popov VM, Jiao X, Lisanti MP, Casola A, Pestell RG (May 2008). "Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8". Proceedings of the National Academy of Sciences of the United States of America. 105 (19): 6924–9. doi:10.1073/pnas.0802085105. PMC 2374551. PMID 18467491.
29. Watanabe, Akira; Ogiwara, Hideki; Ehata, Shogo; Mukasa, Akitake; Ishikawa, Shumpei; Maeda, Daichi; Ueki, Keisuke; Ino, Yasushi; Todo, Tomoki (2011-07-26). "Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells". Proceedings of the National Academy of Sciences of the United States of America. 108 (30): 12384–12389. doi:10.1073/pnas.0906930108. ISSN 0027-8424. PMC 3145721. PMID 21750150.
30. Schild R, Knüppel T, Konrad M, Bergmann C, Trautmann A, Kemper MJ, Wu K, Yaklichkin S, Wang J, Pestell R, Müller-Wiefel DE, Schaefer F, Weber S (January 2013). "Double homozygous missense mutations in DACH1 and BMP4 in a patient with bilateral cystic renal dysplasia". Nephrology, Dialysis, Transplantation. 28 (1): 227–32. doi:10.1093/ndt/gfs539. PMC 3616761. PMID 23262432.

Further reading

• Hammond KL, Hanson IM, Brown AG, Lettice LA, Hill RE (2003). "Mammalian and Drosophila dachshund genes are related to the Ski proto-oncogene and are expressed in eye and limb". Mech. Dev. 74 (1–2): 121–131. doi:10.1016/S0925-4773(98)00071-9. PMID 9651501.
• Hammond KL, Lettice LA, Hill RE, Lee M, Boyle S, Hanson IM (1999). "Human (DACH) and mouse (Dach) homologues of Drosophila dachshund map to chromosomes 13q22 and 14E3, respectively". Genomics. 55 (2): 252–253. doi:10.1006/geno.1998.5662. PMID 9933575.
• Kozmik Z, Cvekl A (1999). "Localization of the human homologue of the Drosophila dachshund gene (DACH) to chromosome 13q21". Genomics. 59 (1): 110–111. doi:10.1006/geno.1999.5797. PMID 10395809.
• Kozmik Z, Pfeffer P, Kralova J, Paces J, Paces V, Kalousova A, Cvekl A (1999). "Molecular cloning and expression of the human and mouse homologues of the Drosophila dachshund gene". Dev. Genes Evol. 209 (9): 537–545. doi:10.1007/s004270050286. PMID 10502110.
• Machon O, Backman M, Julin K, Krauss S (2001). "Yeast two-hybrid system identifies the ubiquitin-conjugating enzyme mUbc9 as a potential partner of mouse Dac". Mech. Dev. 97 (1–2): 3–12. doi:10.1016/S0925-4773(00)00402-0. PMID 11025202.
• Ayres JA, Shum L, Akarsu AN, Dashner R, Takahashi K, Ikura T, Slavkin HC, Nuckolls GH (2001). "DACH: genomic characterization, evaluation as a candidate for postaxial polydactyly type A2, and developmental expression pattern of the mouse homologue". Genomics. 77 (1–2): 18–26. doi:10.1006/geno.2001.6618. PMID 11543628.
• Ozaki H, Watanabe Y, Ikeda K, Kawakami K (2002). "Impaired interactions between mouse Eyal harboring mutations found in patients with branchio-oto-renal syndrome and Six, Dach, and G proteins". J. Hum. Genet. 47 (3): 0107–0116. doi:10.1007/s100380200011. PMID 11950062.
• Ikeda K, Watanabe Y, Ohto H, Kawakami K (2002). "Molecular interaction and synergistic activation of a promoter by Six, Eya, and Dach proteins mediated through CREB binding protein". Mol. Cell. Biol. 22 (19): 6759–6766. doi:10.1128/MCB.22.19.6759-6766.2002. PMC 134036. PMID 12215533.
• Wu K, Yang Y, Wang C, Davoli MA, D'Amico M, Li A, Cveklova K, Kozmik Z, Lisanti MP, Russell RG, Cvekl A, Pestell RG (2004). "DACH1 inhibits transforming growth factor-beta signaling through binding Smad4". J. Biol. Chem. 278 (51): 51673–51684. doi:10.1074/jbc.M310021200. PMID 14525983.
• Nobrega MA, Ovcharenko I, Afzal V, Rubin EM (2003). "Scanning human gene deserts for long-range enhancers". Science. 302 (5644): 413. doi:10.1126/science.1088328. PMID 14563999.
• Li X, Oghi KA, Zhang J, Krones A, Bush KT, Glass CK, Nigam SK, Aggarwal AK, Maas R, Rose DW, Rosenfeld MG (2003). "Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis". Nature. 426 (6964): 247–254. doi:10.1038/nature02083. PMID 14628042.
• Martini SR, Davis RL (2005). "The dachshund gene is required for the proper guidance and branching of mushroom body axons in Drosophila melanogaster". J. Neurobiol. 64 (2): 133–144. doi:10.1002/neu.20130. PMID 15818552.
• Wu K, Li A, Rao M, Liu M, Dailey V, Yang Y, Di Vizio D, Wang C, Lisanti MP, Sauter G, Russell RG, Cvekl A, Pestell RG (2006). "DACH1 is a cell fate determination factor that inhibits cyclin D1 and breast tumor growth". Mol. Cell. Biol. 26 (19): 7116–7129. doi:10.1128/MCB.00268-06. PMC 1592900. PMID 16980615.