Omneity® Pellets
All-In-One Vitamin & Mineral Pellet
Identification of a melanocyte-specific, microphthalmia-associated transcription factor-dependent regulatory element in the intronic duplication causing hair greying and melanoma in horses.
Abstract: Greying with age in horses is an autosomal dominant trait, characterized by hair greying, high incidence of melanoma and vitiligo-like depigmentation. Previous studies have revealed that the causative mutation for this phenotype is a 4.6-kb intronic duplication in STX17 (Syntaxin 17). By using reporter constructs in transgenic zebrafish, we show that a construct containing two copies of the duplicated sequence acts as a strong enhancer in neural crest cells and has subsequent melanophore-specific activity during zebrafish embryonic development whereas a single copy of the duplicated sequence acts as a weak enhancer, consistent with the phenotypic manifestation of the mutation in horses. We further used luciferase assays to investigate regulatory regions in the duplication, to reveal tissue-specific activities of these elements. One region upregulated the reporter gene expression in a melanocyte-specific manner and contained two microphthalmia-associated transcription factor (MITF) binding sites, essential for the activity. Microphthalmia-associated transcription factor regulates melanocyte development, and these binding sites are outstanding candidates for mediating the melanocyte-specific activity of the element. These results provide strong support for the causative nature of the duplication and constitute an explanation for the melanocyte-specific effects of the Grey allele.
© 2011 John Wiley & Sons A/S.
Publication Date: 2011-09-21 PubMed ID: 21883983DOI: 10.1111/j.1755-148X.2011.00902.xGoogle Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
This research paper delves into the genetic causes behind the graying of horse hair over time, the high occurrence of melanoma, and the vitiligo-like depigmentation in horses. The study discovered that a duplicated sequence in the Syntaxin 17 (STX17) gene acts as a significant enhancer in neural crest cells, thus affecting color changes in horses.
Understanding the Genetic Mutation
- The study begins by stating that greying with age in horses is an autosomal dominant trait associated with hair greying, high probability of melanoma, and vitiligo-like depigmentation (loss of skin color).
- It was previously discovered that this trait is due to a 4.6-kb intronic duplication in STX17 (Syntaxin 17) gene. The duplication refers to an event where a part of the DNA sequence is repeated.
Testing the Influence of the Duplicated Sequence
- To understand the influence of this duplicated sequence, the research used reporter constructs in transgenic zebrafish, acting as a model organism.
- The findings showed that a construct containing two copies of the duplicated sequence functions as a strong enhancer in neural crest cells during the embryonic development of the zebrafish. These cells are precursors to melanocytes – pigment producing cells responsible for color.
- Conversely, a single copy of the duplicated sequence displayed weaker enhancing effects, aligning with the observed graying manifestation in horses.
Investigation of Regulatory Regions
- Further examination through luciferase assays focused on the regulatory regions within the duplication. Luciferase assays are a common technique to study gene expression.
- One particular region significantly increased reporting gene expression specifically in melanocytes – this is where the color change occurs. Within this region, two binding sites for Microphthalmia-associated transcription factor (MITF) were located.
- MITF regulates melanocyte development and these identified binding sites are potential mediators of its melanocyte-specific activity. These promising candidates may be responsible for the hair and skin color changes associated with the Grey allele in horses.
Significance of the Study
- This study provides a plausible explanation for the melanocyte-specific effects of the Grey allele in horses, further supporting the previous hypothesis of the causative nature of STX17 duplication.
- This new insight into the genetic causes behind these conditions in horses could contribute to better understanding of human diseases like melanoma and vitiligo, as the genetic fundamentals are shared across mammals.
Cite This Article
APA
Sundström E, Komisarczuk AZ, Jiang L, Golovko A, Navratilova P, Rinkwitz S, Becker TS, Andersson L.
(2011).
Identification of a melanocyte-specific, microphthalmia-associated transcription factor-dependent regulatory element in the intronic duplication causing hair greying and melanoma in horses.
Pigment Cell Melanoma Res, 25(1), 28-36.
https://doi.org/10.1111/j.1755-148X.2011.00902.x Publication
Researcher Affiliations
- Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
MeSH Terms
- Aging / genetics
- Animals
- Animals, Genetically Modified
- Binding Sites
- Enhancer Elements, Genetic
- Gene Dosage
- Gene Duplication
- Gene Expression Regulation, Developmental
- Genes, Dominant
- Genes, Reporter
- Hair Color / genetics
- Horse Diseases / genetics
- Horses / genetics
- Humans
- Introns / genetics
- Mammals
- Melanocytes / metabolism
- Melanoma / genetics
- Melanoma / veterinary
- Melanophores / metabolism
- Microphthalmia-Associated Transcription Factor / metabolism
- Neural Crest / cytology
- Phenotype
- Qa-SNARE Proteins / genetics
- Qa-SNARE Proteins / physiology
- Skin Neoplasms / genetics
- Skin Neoplasms / veterinary
- Species Specificity
- Zebrafish
Citations
This article has been cited 22 times.- Pimenta J, Prada J, Cotovio M. Equine Melanocytic Tumors: A Narrative Review. Animals (Basel) 2023 Jan 10;13(2).
- Andersson L, Purugganan M. Molecular genetic variation of animals and plants under domestication. Proc Natl Acad Sci U S A 2022 Jul 26;119(30):e2122150119.
- Li J, Lee MO, Davis BW, Wu P, Hsieh Li SM, Chuong CM, Andersson L. The crest phenotype in domestic chicken is caused by a 197 bp duplication in the intron of HOXC10. G3 (Bethesda) 2021 Feb 9;11(2).
- Weber LA, Funtan A, Paschke R, Delarocque J, Kalbitz J, Meißner J, Feige K, Kietzmann M, Cavalleri JV. In vitro assessment of triterpenoids NVX-207 and betulinyl-bis-sulfamate as a topical treatment for equine skin cancer. PLoS One 2020;15(11):e0241448.
- Minnoye L, Taskiran II, Mauduit D, Fazio M, Van Aerschot L, Hulselmans G, Christiaens V, Makhzami S, Seltenhammer M, Karras P, Primot A, Cadieu E, van Rooijen E, Marine JC, Egidy G, Ghanem GE, Zon L, Wouters J, Aerts S. Cross-species analysis of enhancer logic using deep learning. Genome Res 2020 Dec;30(12):1815-1834.
- van der Weyden L, Brenn T, Patton EE, Wood GA, Adams DJ. Spontaneously occurring melanoma in animals and their relevance to human melanoma. J Pathol 2020 Sep;252(1):4-21.
- Weber LA, Meißner J, Delarocque J, Kalbitz J, Feige K, Kietzmann M, Michaelis A, Paschke R, Michael J, Pratscher B, Cavalleri JV. Betulinic acid shows anticancer activity against equine melanoma cells and permeates isolated equine skin in vitro. BMC Vet Res 2020 Feb 5;16(1):44.
- Domyan ET, Hardy J, Wright T, Frazer C, Daniels J, Kirkpatrick J, Kirkpatrick J, Wakamatsu K, Hill JT. SOX10 regulates multiple genes to direct eumelanin versus pheomelanin production in domestic rock pigeon. Pigment Cell Melanoma Res 2019 Sep;32(5):634-642.
- van der Weyden L, Patton EE, Wood GA, Foote AK, Brenn T, Arends MJ, Adams DJ. Cross-species models of human melanoma. J Pathol 2016 Jan;238(2):152-65.
- Dorshorst B, Harun-Or-Rashid M, Bagherpoor AJ, Rubin CJ, Ashwell C, Gourichon D, Tixier-Boichard M, Hallböök F, Andersson L. A genomic duplication is associated with ectopic eomesodermin expression in the embryonic chicken comb and two duplex-comb phenotypes. PLoS Genet 2015 Mar;11(3):e1004947.
- Jiang L, Campagne C, Sundström E, Sousa P, Imran S, Seltenhammer M, Pielberg G, Olsson MJ, Egidy G, Andersson L, Golovko A. Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses. BMC Cancer 2014 Nov 21;14:857.
- Wang Y, Tang Z, Sun Y, Wang H, Wang C, Yu S, Liu J, Zhang Y, Fan B, Li K, Liu B. Analysis of genome-wide copy number variations in Chinese indigenous and western pig breeds by 60 K SNP genotyping arrays. PLoS One 2014;9(9):e106780.
- Seltenhammer MH, Sundström E, Meisslitzer-Ruppitsch C, Cejka P, Kosiuk J, Neumüller J, Almeder M, Majdic O, Steinberger P, Losert UM, Stöckl J, Andersson L, Sölkner J, Vetterlein M, Golovko A. Establishment and characterization of a primary and a metastatic melanoma cell line from Grey horses. In Vitro Cell Dev Biol Anim 2014 Jan;50(1):56-65.
- Curik I, Druml T, Seltenhammer M, Sundström E, Pielberg GR, Andersson L, Sölkner J. Complex inheritance of melanoma and pigmentation of coat and skin in Grey horses. PLoS Genet 2013;9(2):e1003248.
- Jabbari A, Petukhova L, Cabral RM, Clynes R, Christiano AM. Genetic basis of alopecia areata: a roadmap for translational research. Dermatol Clin 2013 Jan;31(1):109-17.
- Rubin CJ, Megens HJ, Martinez Barrio A, Maqbool K, Sayyab S, Schwochow D, Wang C, Carlborg Ö, Jern P, Jørgensen CB, Archibald AL, Fredholm M, Groenen MA, Andersson L. Strong signatures of selection in the domestic pig genome. Proc Natl Acad Sci U S A 2012 Nov 27;109(48):19529-36.
- Sundström E, Imsland F, Mikko S, Wade C, Sigurdsson S, Pielberg GR, Golovko A, Curik I, Seltenhammer MH, Sölkner J, Lindblad-Toh K, Andersson L. Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses. BMC Genomics 2012 Aug 2;13:365.
- Sitaram A, Marks MS. Mechanisms of protein delivery to melanosomes in pigment cells. Physiology (Bethesda) 2012 Apr;27(2):85-99.
- Rubin CJ, Hodge M, Naboulsi R, Beckman M, Bellone RR, Kallenberg A, J'Usrey S, Ohmura H, Seki K, Furukawa R, Ohnuma A, Davis BW, Tozaki T, Lindgren G, Andersson L. An intronic copy number variation in Syntaxin 17 determines speed of greying and melanoma incidence in Grey horses. Nat Commun 2024 Aug 29;15(1):7510.
- Zscherpe P, Kalbitz J, Weber LA, Paschke R, Mäder K, von Rechenberg B, Cavalleri JV, Meißner J, Klein K. Potent drug delivery enhancement of betulinic acid and NVX-207 into equine skin in vitro - a comparison between a novel oxygen flow-assisted transdermal application device and microemulsion gels. BMC Vet Res 2024 May 16;20(1):202.
- Andersson L. White horses - non-coding sequences drive premature hair greying and predisposition to melanoma. Ups J Med Sci 2024;129.
- Giovannini S, Strillacci MG, Bagnato A, Albertini E, Sarti FM. Genetic and Phenotypic Characteristics of Belted Pig Breeds: A Review. Animals (Basel) 2023 Sep 30;13(19).
Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists
