Epigenetic determinants of optimal skin response to UV radiation
Lead Research Organisation:
University of Manchester
Department Name: School of Biological Sciences
Abstract
The aim of this ICASE PhD project is to investigate the effects of UV radiation on skin ageing, using novel epigenetic techniques. The research is in partnership with Unilever R&D.
Ageing skin is characterised by a number of well-documented biological changes including altered architecture of the dermal matrix (e.g. 'elastosis' and remodelling of the elastic fibre network, changes in collagen and matrix metalloproteinase gene expression, DNA damage and an increase in the presence of senescent cells. However, less in known about the exact mechanisms through which these changes occur and become stable features of aged skin.
Epigenetics is a new and exciting field that is offering novel insights in the biology of ageing. Recent advances in technologies to study epigenetic changes, particularly DNA methylation, are furthering the understanding of cellular control of biological pathways and how this is dysregulated with increasing age. In part, this is due to the stable nature of DNA methylation which means, as well as a determinant of gene activity/expression, it is a good marker of historic environmental exposures. For example, methylation differences have been found in developmental body patterning genes in skin fibroblasts from different body sites indicating the fibroblasts had a 'memory' of environmental exposures during development. Hence, epigenetics is a particularly promising field for skin ageing research.
It is likely that the accumulated exposure of skin cells to environmental stressors (e.g. ultraviolet [UV] radiation) is reflected by variance in DNA methylation levels which influence the activities of nearby genes. These differentially methylated regions (DMRs) will therefore pinpoint the genes most affected by repeated exposure to stressors. How such epigenetic changes influence the response of aged skin to new stressor exposure is unclear, but could offer new routes for rejuvenating the skin or preventing the accumulation of damage.
Within the UK, most if not nearly all of the population will have regular UV radiation exposure 'challenges' to their skin during the summer. Although much research has focussed on single high UV radiation doses (i.e. greater than 3 times the minimal erythemal dose [MED]), little work has focussed on multiple low dose exposures, comparable to that attained in vivo. Indeed, it can be argued that for most UK nationals, multiple low dose UV radiation exposures are a greater driver of skin ageing than short very high doses. Hence, we propose to investigate the affects of multiple low doses of an environmental stressor (e.g. UV exposure of 40-80% of the MED, typical of 20 minutes skin type III in the midday sun) on methylation levels across the human genome in young and old skin.
The research will therefore follow four distinct phases:
- Determining the level of epigenetic change following solar simulated exposures in vivo.
- Identifying epigenetic skin response in vivo to solar simulated radiation
- Validation of methylation differences at the protein and/or mRNA level in vivo
- Correlation of DMRs to makers of cellular and tissue damage.
Ageing skin is characterised by a number of well-documented biological changes including altered architecture of the dermal matrix (e.g. 'elastosis' and remodelling of the elastic fibre network, changes in collagen and matrix metalloproteinase gene expression, DNA damage and an increase in the presence of senescent cells. However, less in known about the exact mechanisms through which these changes occur and become stable features of aged skin.
Epigenetics is a new and exciting field that is offering novel insights in the biology of ageing. Recent advances in technologies to study epigenetic changes, particularly DNA methylation, are furthering the understanding of cellular control of biological pathways and how this is dysregulated with increasing age. In part, this is due to the stable nature of DNA methylation which means, as well as a determinant of gene activity/expression, it is a good marker of historic environmental exposures. For example, methylation differences have been found in developmental body patterning genes in skin fibroblasts from different body sites indicating the fibroblasts had a 'memory' of environmental exposures during development. Hence, epigenetics is a particularly promising field for skin ageing research.
It is likely that the accumulated exposure of skin cells to environmental stressors (e.g. ultraviolet [UV] radiation) is reflected by variance in DNA methylation levels which influence the activities of nearby genes. These differentially methylated regions (DMRs) will therefore pinpoint the genes most affected by repeated exposure to stressors. How such epigenetic changes influence the response of aged skin to new stressor exposure is unclear, but could offer new routes for rejuvenating the skin or preventing the accumulation of damage.
Within the UK, most if not nearly all of the population will have regular UV radiation exposure 'challenges' to their skin during the summer. Although much research has focussed on single high UV radiation doses (i.e. greater than 3 times the minimal erythemal dose [MED]), little work has focussed on multiple low dose exposures, comparable to that attained in vivo. Indeed, it can be argued that for most UK nationals, multiple low dose UV radiation exposures are a greater driver of skin ageing than short very high doses. Hence, we propose to investigate the affects of multiple low doses of an environmental stressor (e.g. UV exposure of 40-80% of the MED, typical of 20 minutes skin type III in the midday sun) on methylation levels across the human genome in young and old skin.
The research will therefore follow four distinct phases:
- Determining the level of epigenetic change following solar simulated exposures in vivo.
- Identifying epigenetic skin response in vivo to solar simulated radiation
- Validation of methylation differences at the protein and/or mRNA level in vivo
- Correlation of DMRs to makers of cellular and tissue damage.
People |
ORCID iD |
| Rachel Watson (Primary Supervisor) | |
| Bethany Barnes (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/N503599/1 | 01/10/2015 | 30/09/2019 | |||
| 1640517 | Studentship | BB/N503599/1 | 01/10/2015 | 30/09/2019 | Bethany Barnes |
| Description | Skin is subject to direct and damaging encounters with our environment. Sunlight, containing ultraviolet (UV) radiation, is a key driver of skin cancer and can accelerate the appearance of ageing (causing wrinkles, changes in pigmentation (sunspots) and loss of skin elasticity). UV radiation is known to cause damage to our genetic material, causing mutations that negatively affect how our skin functions. Our epigenetics have also recently been reported to be affected by UV radiation. Epigenetics refers to changes in the expression of genes that occurs without direct damage to the sequence of our DNA. This includes DNA methylation, which describes the chemical addition of a small chemical modification called a methyl group to be added or removed from the DNA. This acts as a chemical switch, causing a gene to be switched on or off. The aims of the study were to assess the impact of multiple low-level exposures to UV radiation affects epigenetics in young and aged volunteers. In the young group, we identified no changes in response to UV radiation that met our stringent statistical criteria. We then looked at changes occurring in aged skin in response to UV radiation, identifying 366 differentially methylated sites. Of these, the majority were loss of methylation at a ratio of 15:1. This suggests that epigenetic damage occurs to a much greater extent in aged skin than young. This is the first time that increased amount of damage at the epigenetic level has been shown in human volunteers as a result of the age of the individual, suggesting that aged skin is impaired compared to young and loses the ability to repair and protect its epigenetics. |
| Exploitation Route | Our data showed that aged skin is impaired in its ability to protect, or repair, its epigenetics. The cellular deficiencies that govern this may offer new insights into skin cancer risk and skin ageing, including aesthetic as well as functional consequences. |
| Sectors | Education,Environment,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Description | Manchester Institute for Collaborative Research on Ageing |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | An oral presentation discussing aspects of the PhD project at an event for the Manchester Institute for Collaborative Research on Ageing, attended by postgraduate students and faculty members from many different disciplines, including medicine, sociology and psychology. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Manchester Science Festival at Manchester Museum |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | A day of activities for children to better understand dermatology research. Children could look at their own fingerprints, look at their own skin cells and make UV-reactive bead bracelets. |
| Year(s) Of Engagement Activity | 2016 |
| Description | Oral presentation at British Society for Investigative Dermatology (April 2019) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | Oral talk to be given at the British Society for Investigative Dermatology in April 2019. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Poster presentation at British Society for Investigative Dermatology (April 2017) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | Poster presentation showing work completed in years 1-2 of this PhD project. |
| Year(s) Of Engagement Activity | 2017 |
| Description | Poster presentation at European Society for Dermatological Research (2018) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Poster presentation of work completed in years 1-2 of this PhD project. Abstract was published in Journal of Investigative dermatology, DOI given below. |
| Year(s) Of Engagement Activity | 2018 |
| Description | School visit (Greater Manchester) |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | Organised and ran a two 2 hour workshop for years 1 and 2 at a local primary school. The aim of the workshop was to raise awareness of sun safety, a subject which related directly to my PhD project. The children were heavily enthused by the afternoons activities, and were eager to educate their parents at home time.The workshop also gave the children a glimpse into the life of a scientist beyond the classroom, with many exclaiming that they wanted to grow up to be scientists. The workshop began with a short presentation with heavy involvement of the children, who were asked questions and their opinions on sun safety. This also introduced the idea of your skin being formed from many different cells that can become damaged, and we likened this to craft beads that we had purchased, which glowed when exposed to UV light. The rest of the workshop was in the form of a 'carousel' -- groups of 8 children moved around different activities for twenty minutes each. The activities were as follows:- 1) A petri dish where the 'UV' beads had been tacked down. The children covered the lid of the petri dish with different sun creams that they had been asked to bring in from home and investigated the effects of different levels of SPF and UV lamp we provided. We also provided carrot oil for comparison, which causes the beads to glow brighter than if no cream had been applied. 2) Making keyrings to put on their school bags using the 'UV' beads and other beads to spell out their names.This will remind them when the beads glow, that there is high levels of UV and they should wear sun protection or seek shade. 3) We provided a 'toy'microscope so that they could visualise their own skin cells. This involved putting sellotape on the back of their hands, peeling it off and placing it on a microscope slide. As the tape only peels the top few cells from the hand, the appearance of the cells appeared like the beads they were using throughout the day. 4) DNA extraction from strawberries 5-6) independent work using ipads -- the children were asked to a series of questions which they were allowed to use the ipads to find the answers - and colouring-in exercise that listed the different ways of being sun safe (e.g. wear a hat, sun cream, long sleeved clothing, seek shade) |
| Year(s) Of Engagement Activity | 2018 |
| Description | Science Spectacular at Museum of Science and Industry |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | A day of activities for children to better understand dermatology research. Children could look at their own fingerprints, look at their own skin cells and make UV-reactive bead bracelets. |
| Year(s) Of Engagement Activity | 2017 |