A direct link between MITF, innate immunity, and hair graying

Harris, Melissa L.; Fufa, Temesgen; Palmer, Joseph W.; Joshi, Sandeep S.; Larson, Denise M.; Incao, Arturo; Gildea, Derek; Trivedi, Niraj; Lee, Autumne N; Day, Chi-Ping; Michael, Helen; Hornyak, Thomas J.; Merlino, Glenn; Program, Nisc Comparative Sequencing; Pavan, William J.

doi:10.1371/journal.pbio.2003648

Cited by 76 publications

(61 citation statements)

References 87 publications

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“…Next, we aimed to understand how stress transmits signals to the periphery to alter MeSCs biology. Immune attack has been postulated to be the underlying cause of the Marie Antoinette syndrome 33,34 , and stress is thought to lead to changes in immune cell composition and immune responses 35 . To test the involvement of the immune system, we injected RTX into Rag1 mutant mice, which lack both T cells and B cells, and into CD11b-DTR mice, in which myeloid lineages had been ablated by diphtheria toxin (DT).…”

Section: Norepinephrine Drives Hair Greying By Acting On Mescs Directlymentioning

confidence: 99%

Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells

Zhang

Rachmin

et al. 2020

Nature

195

177

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Stress is an out of the norm state caused by emotional or physical insults. While chronic stress is considered harmful, acute stress is thought to cause transient and reversible changes essential for fight or flight. Stress has been anecdotally associated with hair greying, but scientific evidence linking the two is scant. Here, using mouse stress models, we found that acute stress leads to hair greying through rapid depletion of melanocyte stem cells (MeSCs). Combining adrenalectomy, denervation, chemogenetics, cell ablation, and MeSC-specific adrenergic receptor knockout, we found that stress-induced MeSC loss is independent of the immune attack or adrenal hormones. Instead, hair greying results from activation of the sympathetic nervous system that innervates the MeSC niche. Upon stress, sympathetic nerve activation leads to burst release of the neurotransmitter norepinephrine, which acts directly on MeSCs. Norepinephrine drives quiescent MeSCs to proliferate rapidly, followed by migration and differentiation, leading to their permanent depletion from the niche. Transient suppression of MeSC proliferation with topical application of cell cycle inhibitors rescues stress-induced hair greying. Our studies demonstrate that stress-induced neuronal activity can be an upstream trigger that forces stem cells out of quiescence, and suggest that acute stress stimuli can be more detrimental than anticipated by causing rapid and irreversible loss of somatic stem cells.

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Section: Norepinephrine Drives Hair Greying By Acting On Mescs Directlymentioning

confidence: 99%

Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells

Zhang

Rachmin

et al. 2020

Nature

195

177

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“…We anticipate these genes represent candidates that may alter intrinsic McSC dynamics at the protein level, either through differential transcript expression or as the consequence of genetic variation in their coding sequence. Using a previously published RNAseq dataset (Harris et al 2018), we generated a list of expression values from C57BL/6J wildtype McSCs isolated from dormant (telogen-stage) hairs. These gene expression values represent the read counts per gene after normalization using the median ratio method (DESeq2).…”

Section: Resultsmentioning

confidence: 99%

Identification of Gene Variants Associated with Melanocyte Stem Cell Differentiation in Mice Predisposed for Hair Graying

Fialkowski¹,

Levy

Watkins‐Chow

et al. 2019

G3 Genes|Genomes|Genetics

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Age-related hair graying is caused by malfunction in the regenerative potential of the adult pigmentation system. The retention of hair color over the life of an organism is dependent on the ability of the melanocyte stem cells and their progeny to produce pigment each time a new hair grows. Age-related hair graying is variable in association with genetic background suggesting that quantitative trait loci influencing this trait can be identified. Identification of these quantitative trait loci may lead to the discovery of novel and interesting genes involved in stem cell biology and/or melanogenesis. With this in mind we developed previously a sensitized, mouse modifier screen and discovered that the DBA/1J background is particularly resistant to melanocyte stem cell differentiation in comparison to the C57BL/6J background. Melanocyte stem cell differentiation generally precedes hair graying and is observed in melanocyte stem cells with age. Using quantitative trait loci analysis, we have now identified three quantitative trait loci on mouse chromosomes 7, 13, and X that are associated with DBA/1J-mediated variability in melanocyte stem cell differentiation. Taking advantage of publicly-available mouse sequence and variant data, in silico protein prediction programs, and whole genome gene expression results we describe a short list of potential candidate genes that we anticipate to be involved in melanocyte stem cell biology in mice.

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“…The list of genes implicated in hair greying phenotype include loci previously linked with smoking status ( KIF1A , RUNX1 , IRF4 , BRINP1 , TEX41 , GRID1 ), BMI/obesity ( GRID1 , TEX41 , SEMA4D , TBC1D22A , RUNX1 ), bone mineral density ( RUNX1 , TBC1D22A, TEX41 ), cardiovascular diseases ( FGF5 , MROH2A , DPEP1 , GRID1 ) and immunology ( RUNX1 , TBC1D22A, IRF4, TMEM132C, GRID1). Importantly, all the above mentioned factors (particularly smoking) were linked with hair greying syndrome in previous research and therefore the link between these genes and greying seems to be justified [ 16 , 33 – 36 ]. Three genes have been previously linked with ageing effects, that is longevity ( TBC1D22A ), skin aging ( IRF4 ) and DNA methylation aging ( RUNX1 ) [ 37 – 39 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring the possibility of predicting human head hair greying from DNA using whole-exome and targeted NGS data

et al. 2020

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Background Greying of the hair is an obvious sign of human aging. In addition to age, sex- and ancestry-specific patterns of hair greying are also observed and the progression of greying may be affected by environmental factors. However, little is known about the genetic control of this process. This study aimed to assess the potential of genetic data to predict hair greying in a population of nearly 1000 individuals from Poland. Results The study involved whole-exome sequencing followed by targeted analysis of 378 exome-wide and literature-based selected SNPs. For the selection of predictors, the minimum redundancy maximum relevance (mRMRe) method was used, and then two prediction models were developed. The models included age, sex and 13 unique SNPs. Two SNPs of the highest mRMRe score included whole-exome identified KIF1A rs59733750 and previously linked with hair loss FGF5 rs7680591. The model for greying vs. no greying prediction achieved accuracy of cross-validated AUC = 0.873. In the 3-grade classification cross-validated AUC equalled 0.864 for no greying, 0.791 for mild greying and 0.875 for severe greying. Although these values present fairly accurate prediction, most of the prediction information was brought by age alone. Genetic variants explained < 10% of hair greying variation and the impact of particular SNPs on prediction accuracy was found to be small. Conclusions The rate of changes in human progressive traits shows inter-individual variation, therefore they are perceived as biomarkers of the biological age of the organism. The knowledge on the mechanisms underlying phenotypic aging can be of special interest to the medicine, cosmetics industry and forensics. Our study improves the knowledge on the genetics underlying hair greying processes, presents prototype models for prediction and proves hair greying being genetically a very complex trait. Finally, we propose a four-step approach based on genetic and epigenetic data analysis allowing for i) sex determination; ii) genetic ancestry inference; iii) greying-associated SNPs assignment and iv) epigenetic age estimation, all needed for a final prediction of greying.

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A direct link between MITF, innate immunity, and hair graying

Cited by 76 publications

References 87 publications

Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells

Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells

Identification of Gene Variants Associated with Melanocyte Stem Cell Differentiation in Mice Predisposed for Hair Graying

Exploring the possibility of predicting human head hair greying from DNA using whole-exome and targeted NGS data

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