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
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- Journal Article
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- Non-U.S. Gov't
Summary
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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
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