At first glance, the Epigenetic Control of Skin Development and Regeneration meeting didn’t look like the same old epigenetic conference that we’re used to seeing, so we were excited to see what it would be like. Thanks to the conference organizers, we were able to have Tanya Shaw from St George’s, University of London attend and report back to us on all the epigenetic happenings in the epidermis. Check out the action from this inaugural event:
Epigenetic Control of Skin Development and Regeneration Overview
The First International Symposium on “Epigenetic Control of Skin Development and Regeneration” was hosted by the Centre for Skin Sciences at the University of Bradford on the 2nd and 3rd of April, 2012. The conference was organized by Prof. Vladimir Botchkarev, Dr. Mike Fessing, Dr. Natalia Botchkareva, Dr. Gill Westgate and Prof. Des Tobin and brought together an international and truly world-class collection of researchers in a lovely new facility on the University of Bradford campus. The schedule provided a good amount of time for interaction and discussion over delicious pastries and lunches, and the Gala Evening at the National Media Museum was a fantastic place to get to know one another while pretending to be news presenters, sitcom stars or Teletubbies!
Even before we relaxed at the Gala, there was a true sense of mutual support and encouragement in the air. This was likely a reflection of the impressive collaborative work that is taking place at the Centre for Skin Sciences. It seems as though the Bradford-based organisers invited collaborators and colleagues, old and new, to pull together the impressive line-up of speakers. And everyone in the audience benefited greatly from hearing about the latest advances in many joint projects.
The whole thing kicked off with Professor Wolf Reik from the Babraham Institute, in Cambridge declaring that he doesn’t know anything about skin! The audience giggled, but this was in fact part of the beauty of this symposium; yes, it showcased the top researchers of the “skin epigenetics” field, but it also brought in the likes of Wolf to tell us about the latest epigenetic discoveries, and to inspire us to apply novel techniques to our skin-specific research questions.
DNA Demethylation During Development
Wolf Reik, Babraham Institute
Prof. Reik’s talk focused on developmental DNA demethylation. The epigenetic community waited for so long for the mechanisms of demethylation to be unveiled, and it was not long ago that his group and others published their important findings that hydroxylation, deamination, and oxidization are initial steps required for the ultimate erasure of DNA methylation. Reik’s presentation gave us the punchline of their research into the TET1/2/3 enzymes, which are responsible for hydroxylating methylated cytosines. We learned that TET3 is the predominant hydroxylase in the zygote and its contribution to reprogramming by driving the complete erasure of DNA methylation is important for somatic cell nuclear transfer success. TET1 and TET2, on the other hand, were discussed for their variable roles in regulating the pleuripotency of embryonic, epiblast, and induced pleuripotent stem cells.
The strongest take-home message from Reik was actually technical in nature. Many of us rely on bisulfite sequencing to determine the methylation status of DNA in regions of interest; however, this approach is unable to distinguish between an unadulterated methylation and the hydroxylated variety. Wolf and his team have been busy devising a clever method for detecting hydroxymethylcytosine to a single base pair resolution. We look forward to hearing the fine details of this assay, and then seeing what it uncovers in terms of exciting roles for transient changes in DNA methylation during skin development and regeneration.
Genomics of Pattern: from Akitas to Zebras
Greg Barsh, Stanford University
During the first afternoon of the meeting, this inaugural symposium provided the forum for the first John Wood Memorial Lecture. Prof. John Wood was described by a Bradford colleague as a remarkable scientist and chemist, whose work focused in part on pigmentation in vitiligo. The recipient of the award was Greg Barsh, who gave a delightful presentation about how he has been able to use forward genetics and genomic approaches (e.g. linkage and association studies, and gene expression analysis) to ask questions such as: how do patterns arise; what developmental pathway(s) underlie periodic patterns; and how are these shaped by evolution? And fascinating is the fact that he is investigating these questions not only in mice, but in dogs, domestic cats, wild felids, and zebras.
Just as an example of the genomic strategy used by Barsh and his team, to study color patterns they have taken biopsies for gene expression analysis from yellow- vs. black-haired skin in wild felids; and black- vs. white-haired skin in zebras. Obviously quantifying transcript abundance in non-model organisms where the genome is not sequenced or well annotated is challenging, but they use a method called EDGE, or EcoP15I-tagged Digital Gene Expression. The altered genes they discover by this method are likely functional contributors to the establishment or implementation of the characteristic patterns of these beautiful animals.
Undertaking a more classic genetics approach in large and wild mammals is also far from easy, but in collaboration with the De Wildt Cheetah Centre in South Africa, where they have an impressively large cheetah pedigree (and cheek swabs for DNA analysis), they have been able to ask, for example, what is the genotype giving rise to the king cheetah phenotype of large coalescing spots?
I have not done justice to Barsh’s eloquent explanation of his approaches, and the data presented went well beyond what I have been able to summarize here, but in terms of take-home messages, a recurring theme from his findings was that the mechanisms regulating the establishment versus the implementation of pigmentation patterns are distinct. In fact, patterns are “established” before melanogenesis even begins. Also, a particularly interesting challenge that he put to us was to consider how copy number variations, and gene duplications may be predisposed to epigenetic modifications, and to remember that extra copies of genes do not necessary mean extra expression.
P63: Regulator of Cellular Integrity
Andrei Mardaryev, University of Bradford Centre for Skin Sciences
The final talk of the entire conference, from Dr. Mardaryev was an ideal conclusion to the meeting, as it tied together many of the topics we’d discussed throughout the two days. He specifically told us about his work on p63, which is indeed “a complex regulator of cellular integrity” that is able to affect the nuclear envelope, histone modifications, polycomb proteins, etc. And although the knock-out is lethal, embryonic analysis has shown profound effects on the epidermis.
His story began with the strangely shaped, deformed and irregular nuclei observed in p63-null cells. There was clearly altered heterochromatin organization, and some lovely images revealed that euchromatin (and active transcription) unusually extended right to the nuclear membrane and filled the nucleus. Other changes in p63-null cells of particular interest to the epigenetic crowd included altered amounts and distribution of the epigenetic modifications histone H3 lysine 9 and 27 tri-methylation, and significant down-regulation of cbx4 (and excitingly, cbx4-/- also has an epidermal phenotype). One p63 target further described by Mardaryev was the cytolinker protein plectin, which may provide an explanation for the striking nuclear phenotype of these cells. Nuclear morphology is a cellular feature that I suspect many of us will keep a closer eye on. And based on the influence that this transcription factor has on many widely investigated epigenetic regulators and modifications, we will also keep a closer eye out for common phenotypes in previously unsuspected places.
Themes and Impressions from the Epigenetic Control of Skin Development and Regeneration Meeting
Having described only a few of the oral presentation, I feel like there are still many important themes and messages from the conference that I have yet to share. Perhaps they have equally stuck with others in attendance and may influence many of us as we move forward as a researchers in the field, so I’ll take the opportunity to share them before closing.
Firstly, as a skin researcher, I usually think about skin for skin’s sake! At this meeting however, skin was repeatedly referred to as a “model”, and indeed skin was re-branded for me as a fantastically accessible “model” of differentiation and development, which is very amenable to screens, often boasting conveniently visual parameters for assessment.
This meeting also provided a fairly comprehensive tour of the many genetic diseases and conditions that can affect the largest organ of our bodies, including cutis laxa, psoriasis, melanoma, and other skin cancers. Clearly the improved understanding of skin biology that we are working towards will have wide-reaching medical benefit. Skin is “funny” in that its pathologies are indisputably a medical problem, but the information gained from research on these topics can be of benefit and interest to the cosmetic industry as well. Accordingly, there were many cosmetic industry-based researchers participating in the symposium, and their sponsorship certainly facilitated the hosting of the event.
An intimidating but exciting realization from the two days was that the roles of all of our favorite epigenetic regulators seem to be cell-type specific, which warrants detailed investigation of their functions in many cellular contexts. There is certainly no shortage of work to be done.
Finally, the almost ubiquitous use of transgenic and knock-out animal models by the presenting scientists was so impressive. Firstly, the developmental importance of many of the epigenetic regulators under investigation means that generation of genetic models requires creative conditional, inducible, and/or cell-type specific strategies, and patience. Moreover, it shows an amazing commitment to fully understand the roles of their proteins of interest, not only in terms of “epigenetics” and alterations in gene expression or histone modifications, but in terms of development, and skin biology.
Congratulations to the researchers who were honored for their presentations:
- Best Poster was awarded to Claire Cox from the Frye lab at the Wellcome Trust Centre for Stem Cell Research
- Best Oral Presentation was given to Dr. Ellen van Rooijen from the Zon lab at Children’s Hospital, Harvard Medical School
Thanks to the organizing committee for assembling such a fantastic symposium.
**EpiGenie would like to thank Tanya Shaw, PhD who is a Lecturer in the Division of Biomedical Sciences at St George’s, University of London for providing this conference coverage.