scholarly journals Selective sweep for an enhancer involucrin allele identifies skin barrier adaptation out of Africa

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mary Elizabeth Mathyer ◽  
Erin A. Brettmann ◽  
Alina D. Schmidt ◽  
Zane A. Goodwin ◽  
Inez Y. Oh ◽  
...  
Keyword(s):  
Selective Sweep ◽  
Skin Barrier ◽  
Human Migration ◽  
Epidermal Differentiation ◽  
Human Populations ◽  
Epidermal Differentiation Complex ◽  
Regulatory Module ◽  
Reporter Assays ◽  
Out Of Africa

AbstractThe genetic modules that contribute to human evolution are poorly understood. Here we investigate positive selection in the Epidermal Differentiation Complex locus for skin barrier adaptation in diverse HapMap human populations (CEU, JPT/CHB, and YRI). Using Composite of Multiple Signals and iSAFE, we identify selective sweeps for LCE1A-SMCP and involucrin (IVL) haplotypes associated with human migration out-of-Africa, reaching near fixation in European populations. CEU-IVL is associated with increased IVL expression and a known epidermis-specific enhancer. CRISPR/Cas9 deletion of the orthologous mouse enhancer in vivo reveals a functional requirement for the enhancer to regulate Ivl expression in cis. Reporter assays confirm increased regulatory and additive enhancer effects of CEU-specific polymorphisms identified at predicted IRF1 and NFIC binding sites in the IVL enhancer (rs4845327) and its promoter (rs1854779). Together, our results identify a selective sweep for a cis regulatory module for CEU-IVL, highlighting human skin barrier evolution for increased IVL expression out-of-Africa.

scholarly journals An enhancer:involucrin regulatory module impacts human skin barrier adaptation out-of-Africa and modifies atopic dermatitis risk

2019 ◽  
Author(s):  
Mary Elizabeth Mathyer ◽  
Erin A. Brettmann ◽  
Alina D. Schmidt ◽  
Zane A. Goodwin ◽  
Ashley M. Quiggle ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Selective Sweep ◽  
Disease Risk ◽  
Skin Barrier ◽  
Loss Of Function ◽  
Regulatory Module ◽  
Reporter Assays ◽  
Out Of Africa ◽  
Selection For ◽  
Skin Epidermis

ABSTRACTThe genetic modules that contribute to human evolution are poorly understood. We identified positive selection for two independent involucrin (IVL) haplotypes in European (CEU) and Asian (JPT/CHB) populations for skin epidermis. CEU IVL associated with increased IVL and a known epidermal-specific enhancer underwent a recent selective sweep out-of-Africa correlating with increased northern latitude. CRISPR/Cas9 deletion of the mouse enhancer revealed enhancer-mediated cis regulation for Ivl expression with human population-specific enhancer reporter assays confirming the additive effect. Furthermore, IVL enhancer eQTLs associated with decreased IVL together with filaggrin loss-of-function variants are enriched in atopic dermatitis cases vs. controls. Together, our enhancer-IVL cis regulatory module findings reveal an emerging paradigm for recently evolved traits to impact skin disease risk in contemporary populations.

scholarly journals Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation

2001 ◽  
Vol 155 (5) ◽  
pp. 821-832 ◽  
Author(s):  
Martyn Chidgey ◽  
Cord Brakebusch ◽  
Erika Gustafsson ◽  
Alan Cruchley ◽  
Chris Hail ◽  
...  
Keyword(s):  
Wound Healing ◽  
Skin Barrier ◽  
Genetically Engineered ◽  
Epidermal Differentiation ◽  
Skin Barrier Function ◽  
Targeted Disruption ◽  
Genetically Engineered Mice ◽  
Barrier Defect ◽  
Strong Adhesion

The desmosomal cadherin desmocollin (Dsc)1 is expressed in upper epidermis where strong adhesion is required. To investigate its role in vivo, we have genetically engineered mice with a targeted disruption in the Dsc1 gene. Soon after birth, null mice exhibit flaky skin and a striking punctate epidermal barrier defect. The epidermis is fragile, and acantholysis in the granular layer generates localized lesions, compromising skin barrier function. Neutrophils accumulate in the lesions and further degrade the tissue, causing sloughing (flaking) of lesional epidermis, but rapid wound healing prevents the formation of overt lesions. Null epidermis is hyperproliferative and overexpresses keratins 6 and 16, indicating abnormal differentiation. From 6 wk, null mice develop ulcerating lesions resembling chronic dermatitis. We speculate that ulceration occurs after acantholysis in the fragile epidermis because environmental insults are more stringent and wound healing is less rapid than in neonatal mice. This dermatitis is accompanied by localized hair loss associated with formation of utriculi and dermal cysts, denoting hair follicle degeneration. Possible resemblance of the lesions to human blistering diseases is discussed. These results show that Dsc1 is required for strong adhesion and barrier maintenance in epidermis and contributes to epidermal differentiation.

scholarly journals Gene duplications and gene loss in the epidermal differentiation complex during the evolutionary land-to-water transition of cetaceans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Karin Brigit Holthaus ◽  
Julia Lachner ◽  
Bettina Ebner ◽  
Erwin Tschachler ◽  
Leopold Eckhart
Keyword(s):  
Genetic Regulation ◽  
Skin Barrier ◽  
Specific Protein ◽  
Epidermal Differentiation ◽  
Major Protein ◽  
Cornified Envelope ◽  
Terrestrial Mammals ◽  
Epidermal Differentiation Complex ◽  
Genes Encoding ◽  
Protein Components

AbstractMajor protein components of the mammalian skin barrier are encoded by genes clustered in the Epidermal Differentiation Complex (EDC). The skin of cetaceans, i.e. whales, porpoises and dolphins, differs histologically from that of terrestrial mammals. However, the genetic regulation of their epidermal barrier is only incompletely known. Here, we investigated the EDC of cetaceans by comparative genomics. We found that important epidermal cornification proteins, such as loricrin and involucrin are conserved and subtypes of small proline-rich proteins (SPRRs) are even expanded in numbers in cetaceans. By contrast, keratinocyte proline rich protein (KPRP), skin-specific protein 32 (XP32) and late-cornified envelope (LCE) genes with the notable exception of LCE7A have been lost in cetaceans. Genes encoding proline rich 9 (PRR9) and late cornified envelope like proline rich 1 (LELP1) have degenerated in subgroups of cetaceans. These data suggest that the evolution of an aquatic lifestyle was accompanied by amplification of SPRR genes and loss of specific other epidermal differentiation genes in the phylogenetic lineage leading to cetaceans.

scholarly journals Fine-mapping the Favored Mutation in a Positive Selective Sweep

2017 ◽  
Author(s):  
Ali Akbari ◽  
Joseph J. Vitti ◽  
Arya Iranmehr ◽  
Mehrdad Bakhtiari ◽  
Pardis C. Sabeti ◽  
...  
Keyword(s):  
Selective Sweep ◽  
Population Genomics ◽  
Simulated Data ◽  
Human Populations ◽  
Selective Sweeps ◽  
1000 Genomes ◽  
Candidate Mutation ◽  
African Populations ◽  
Signature Of Selection ◽  
Out Of Africa

AbstractMethods to identify signatures of selective sweeps in population genomics data have been actively developed, but mostly do not identify the specific mutation favored by the selective sweep. We present a method, iSAFE, that uses a statistic derived solely from population genetics signals to pinpoint the favored mutation even when the signature of selection extends to 5Mbp. iSAFE was tested extensively on simulated data and in human populations from the 1000 Genomes Project, at 22 loci with previously characterized selective sweeps. For 14 of the 22 loci, iSAFE ranked the previously characterized candidate mutation among the 13 highest scoring (out of ∼ 21, 000 variants). Three loci did not show a strong signal. For the remaining loci, iSAFE identified previously unreported mutations as being favored. In these regions, all of which involve pigmentation related genes, iSAFE identified identical selected mutations in multiple non-African populations suggesting an out-of-Africa onset of selection. The iSAFE software can be downloaded from https://github.com/alek0991/iSAFE.

scholarly journals New Treatments for Atopic Dermatitis Targeting Skin Barrier Repair via the Regulation of FLG Expression

2021 ◽  
Vol 10 (11) ◽  
pp. 2506
Author(s):  
Anna Dębińska
Keyword(s):  
Atopic Dermatitis ◽  
Skin Barrier ◽  
Epidermal Differentiation ◽  
Barrier Dysfunction ◽  
New Therapeutic Approaches ◽  
Epidermal Differentiation Complex ◽  
High Prevalence ◽  
New Treatments ◽  
Barrier Repair

Atopic dermatitis (AD) is one of the most common chronic, inflammatory skin disorders with a complex etiology and a broad spectrum of clinical phenotypes. Despite its high prevalence and effect on the quality of life, safe and effective systemic therapies approved for long-term management of AD are limited. A better understanding of the pathogenesis of atopic dermatitis in recent years has contributed to the development of new therapeutic approaches that target specific pathophysiological pathways. Skin barrier dysfunction and immunological abnormalities are critical in the pathogenesis of AD. Recently, the importance of the downregulation of epidermal differentiation complex (EDC) molecules caused by external and internal stimuli has been extensively emphasized. The purpose of this review is to discuss the innovations in the therapy of atopic dermatitis, including biologics, small molecule therapies, and other drugs by highlighting regulatory mechanisms of skin barrier-related molecules, such as filaggrin (FLG) as a crucial pathway implicated in AD pathogenesis.

Genetic Engineering of AAV Capsid Gene for Gene Therapy Application

2020 ◽  
Vol 20 (5) ◽  
pp. 321-332
Author(s):  
Yunbo Liu ◽  
Xu Zhang ◽  
Lin Yang
Keyword(s):  
Gene Therapy ◽  
Neutralizing Antibodies ◽  
Human Subjects ◽  
Genetic Diseases ◽  
Capsid Gene ◽  
Human Populations ◽  
Stable Gene ◽  
Efficient Gene ◽  
Gene Therapy Application

Adeno-associated virus (AAV) is a promising vector for in vivo gene therapy because of its excellent safety profile and ability to mediate stable gene expression in human subjects. However, there are still numerous challenges that need to be resolved before this gene delivery vehicle is used in clinical applications, such as the inability of AAV to effectively target specific tissues, preexisting neutralizing antibodies in human populations, and a limited AAV packaging capacity. Over the past two decades, much genetic modification work has been performed with the AAV capsid gene, resulting in a large number of variants with modified characteristics, rendering AAV a versatile vector for more efficient gene therapy applications for different genetic diseases.

Origin and formation of Yaponesians based on genome sequences

Impact ◽  
2020 ◽  
Vol 2020 (7) ◽  
pp. 56-58
Author(s):  
Naruya Saitou
Keyword(s):  
Population Genetics ◽  
Human Migration ◽  
Human Populations ◽  
Genome Sequences ◽  
Japanese Archipelago ◽  
Broad Term ◽  
The Japanese Archipelago ◽  
Ebb And Flow ◽  
National Institute Of Genetics

The ebb and flow of human migration across the planet can nowadays be probed with advanced archaeology, linguistics, anthropology and genomics. Together, these can provide a convincing picture of the various divergences and convergences of different human populations across vast areas. It is now possible to better understand how, why and where a particular group or society arose. Professor Naruya Saitou of the Population Genetics Laboratory at the National Institute of Genetics in Mishima has dedicated his career to the synthesis of these disciplines. The current focus of his research is on understanding the origins and formation of the Yaponesian people. This broad term was coined by writer Toshio Shimao in 1960s to encompass the diverse peoples of the Japanese Archipelago over its many thousands of years of inhabitation. Saitou's research is helping to uncover Japan's ancient past.

scholarly journals TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
You Shuai ◽  
Zhonghua Ma ◽  
Weitao Liu ◽  
Tao Yu ◽  
Changsheng Yan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Mechanistic Model ◽  
Ectopic Expression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Tissue Samples ◽  
Reporter Assays

Abstract Background Gastric cancer (GC) is the third leading cause of cancer-related mortality globally. Long noncoding RNAs (lncRNAs) are dysregulated in obvious malignancies including GC and exploring the regulatory mechanisms underlying their expression is an attractive research area. However, these molecular mechanisms require further clarification, especially upstream mechanisms. Methods LncRNA MNX1-AS1 expression in GC tissue samples was investigated via microarray analysis and further determined in a cohort of GC tissues via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Cell proliferation and flow cytometry assays were performed to confirm the roles of MNX1-AS1 in GC proliferation, cell cycle regulation, and apoptosis. The influence of MNX1-AS1 on GC cell migration and invasion was explored with Transwell assays. A xenograft tumour model was established to verify the effects of MNX1-AS1 on in vivo tumourigenesis. The TEAD4-involved upstream regulatory mechanism of MNX1-AS1 was explored through ChIP and luciferase reporter assays. The mechanistic model of MNX1-AS1 in regulating gene expression was further detected by subcellular fractionation, FISH, RIP, ChIP and luciferase reporter assays. Results It was found that MNX1-AS1 displayed obvious upregulation in GC tissue samples and cell lines, and ectopic expression of MNX1-AS1 predicted poor clinical outcomes for patients with GC. Overexpressed MNX1-AS1 expression promoted proliferation, migration and invasion of GC cells markedly, whereas decreased MNX1-AS1 expression elicited the opposite effects. Consistent with the in vitro results, MNX1-AS1 depletion effectively inhibited the growth of xenograft tumour in vivo. Mechanistically, TEAD4 directly bound the promoter region of MNX1-AS1 and stimulated the transcription of MNX1-AS1. Furthermore, MNX1-AS1 can sponge miR-6785-5p to upregulate the expression of BCL2 in GC cells. Meanwhile, MNX1-AS1 suppressed the transcription of BTG2 by recruiting polycomb repressive complex 2 to BTG2 promoter regions. Conclusions Our findings demonstrate that MNX1-AS1 may be able to serve as a prognostic indicator in GC patients and that TEAD4-activatd MNX1-AS1 can promote GC progression through EZH2/BTG2 and miR-6785-5p/BCL2 axes, implicating it as a novel and potent target for the treatment of GC.

scholarly journals Lightening Effect of Skin Lightening Cream Containing Piper betle L. Extract in Human Volunteers

Cosmetics ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 32
Author(s):  
Sharifah Shakirah Syed Omar ◽  
Hazrina Hadi ◽  
Nadzira Mohd Hanif ◽  
Hawa Mas Azmar Ahmad ◽  
Shiow-Fern Ng
Keyword(s):  
Particle Size ◽  
Zeta Potential ◽  
Human Subjects ◽  
Skin Barrier ◽  
Skin Tone ◽  
In Vivo Studies ◽  
Piper Betle ◽  
Melanin Content ◽  
Skin Lightening

Hyperpigmentation affects people globally with negative psychological impacts. Piper betle L. leaf (PBL) extract has many benefits including skin lightening which may reduce hyperpigmentation. The objective of this study was to develop an effective skin-lightening cream containing PBL with ideal characteristics. A formulation of base cream and PBL cream was prepared and characterized by centrifugation, particle size and zeta potential analysis, rheological profile studies and physical properties’ observation. In vivo studies on 30 human subjects tested the effects of base and PBL cream on skin-lightening, hydration, trans-epidermal water loss (TEWL) and elasticity through weekly tests 4 weeks in duration. Base and PBL creams had a non-Newtonian property with acceptable color, odor, texture, zeta potential, particle size and showed no phase separation. The in vivo study indicated a significant reduction in melanin content and an improvement in skin tone for PBL cream but not in base cream. TEWL and elasticity also showed significant reduction for both formulations, indicating a healthier skin barrier and supple skin with consistent use, although hydration fluctuated with no significant changes. The developed PBL cream showed significant results in the reduction in melanin content and improving skin tone, which shows the formulation can confer skin-lightening effect.

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