Meet the Editorial Board: A Collection of Insights and Advice from Epigenomics Experts

Keywords::

• bioinformatics
• cancer epigenetics
• early career research
• environmental epigenetics
• epigenetics
• epigenomics

In this Special Feature, several members of the Epigenomics editorial board speak with Storm Johnson (Commissioning Editor, Epigenomics) on topics including the highlights of their career, breakthrough studies, challenging moments, advice for early career researchers, and insights on the future of epigenomics research. In this foreword, I summarize the predominant themes from each interview and touch on the take-home messages from the discussions.

Since its inception, epigenomics research has often been questioned by geneticists and molecular biologists alike.

“At the beginning of my career, scientists were told that if they worked in the field of epigenetics, particularly in cancer research, they would have no career. This was because the dogma at the time was that cancer was solely a genetic disease”, explains Randy Jirtle in his interview ‘The science of hope’ [1].

Jirtle sheds light on the focal points of his career in the face of these challenges, how the Agouti Mouse Study shaped the field, and why the model should be used appropriately. Likewise, Jirtle speaks on the impact of his imprintome research and his concerns over epigenomic nomenclature.

Peter Laird expands upon the lack of recognition epigenomics received, particularly in cancer research, in his interview ‘How epigenomics broke the mold’ [2]. Laird explains his findings in the field of cancer epigenetics and shares his optimism for the future: “I hope and think that going forward, there will be an increasingly integrated view of biology that includes genetic and epigenetic mechanisms as well as their interplay”.

Laird also provides advice for the new generation of epigenomics researchers and reassures early career scientists.

“If everyone is jumping on to the next big thing or the hottest trend, I would advise to not worry about being left behind, but rather to think of your own original ideas. If you pursue your own original research, you will, in the end, end up leading rather than following”, Laird argues.

Next, Moshe Syzf elaborates on his research in early life adversity and the obstacles impeding the study of epigenetic consequences of this in his interview ‘The epigenetics of early life adversity and trauma inheritance’ [3].

“I think the secret that can allow us to move forward in this field is immunology, which has encountered a huge amount of rejection by psychiatrists and molecular psychiatrists … We may not discover the epigenetic programming of specific neuronal circuitries in the brain, and how they really act, but we are closer to uncovering the immune footprint of this phenomenon”, Syzf claims.

Speaking on the controversy surrounding transgenerational epigenetic inheritance, Szyf reveals that “the theory faces rejection because it sounds deterministic, but I think that if you understand what epigenetics is, it’s not deterministic. There is stability, but there’s also room for dynamic change … The history of science is full of examples where ideas essentially took centuries to come up again, because of a priori rejection”.

In the interview ‘Epigenetics in the Anthropocene’ with Oskar Karlsson, Karlsson delves into the need for cross-disciplinary collaboration of epigeneticists with other scientists because of the ties between the exposome and the environment [4].

“We also need to realize that the human exposome and health is closely linked to planetary health. Climate change can for example lead to adverse health effects through heatwaves and increased vector-borne infectious outbreaks … Hence, we need to protect our planet to protect ourselves”, Karlsson explains.

Jacyln Goodrich also expands upon environmental exposure impacts on the epigenome in her interview ‘Insights on exposure-induced disease susceptibility’ [5]. Goodrich describes how there are still improvements yet to be made in legislation protecting people against exposure-induced disease.

“There are thousands of chemicals on the market for which we know little to nothing about their toxicity … Depending on the exposure, susceptible groups could be workers, children, pregnant people, aging adults and/or communities who bear the highest burden of exposure due to environmental racism and injustice”, Goodrich illustrates.

Goodrich also speaks about her work on lipidomics during pregnancy and the effects of the gestational environment on the health of offspring.

“As more and more cohorts generate ‘omics’ datasets like the ones reported in our study, interdisciplinary collaborations between biostatisticians, epidemiologists, toxicologists, clinicians, and computational biologists will be paramount to discovering the biological mechanisms underlying adverse developmental outcomes”, Goodrich points out.

In the interview ‘Epigenetics, environment and epidemiology’ Karl Kelsey describes the interplay between environmental and social risk factors linked with cancer susceptibility and that often social factors may pose significant threat to health than more traditional environmental factors such as toxins [6].

“The SARS-CoV-2 pandemic has helped us understand the health effects of a single exposure in different contexts … The basis of these [social density and viral load] interactions is not solely genetic, molecular, or epigenetic, but it is an example of how exposures can interact with social factors”, Kelsey explains.

Kelsey highlights that “the idea behind understanding what exposures are doing to the epigenome remains a little bit confused because it is very hard to generate that evidence”. Kelsey also gives his opinions on risk prediction models and the challenges in bringing these to the clinic, sharing his optimism that over time, with more data, this may be achievable.

In Jane Skok’s interview titled ‘The art of chromosome dynamics’, Skok describes her work on EpiMethylTag, improvements to imaging technologies, and discusses the recent advances and novel approaches in this field [7].

Skok also praises the support and inspiration of her team – “If you have people with the motivation, passion and expertise you can achieve a lot. This is definitely what makes science fun and exciting as it can take your lab in new directions” – and also describes how “having the input from mentors that have the appropriate computational expertise has made a huge difference to our ability to interpret genome wide data”.

Likewise, Susan Gasser speaks extensively about nuclear organization and imaging technologies in her interview ‘Lessons in chromatin organization and gender equity in research’, highlighting the importance of theoretical modeling approaches [8].

“As analyses become more quantitative, they open the door for comparing and correlating datasets through computational approaches, allowing us to extract principles that can be incorporated into models … Nonetheless, models do not provide answers; rather they produce hypotheses about DNA polymer dynamics and subnuclear compartments, that need to be validated”, Gasser elucidates.

Furthermore, Gasser provides insight on the Women in Science Japan grassroots movement that she helped to establish, highlighting the key lessons learned:

“First, networking is essential. Now with a list of women scientists in Japan, there is a way to share advice or training, to launch collaborations or simply share friendship. Second, one should never underestimate the impact that a few words of encouragement can have. I never would have dreamed that our dinner conversations would have such an impact. Third, one needs to respect – yet not be subservient to – cultural barriers”.

Gasser also points out that “If we could overcome the trend to ‘genderize’ everything, we might reach a state in which we recognize the value of a person’s contribution, independent of gender or race or origin”.

In the interview ‘The ups and downs of DNA methylation’, Gerd Pfeifer illustrates some of the mysteries in DNA methylation research and discusses the work he has conducted in this field [9].

Pfeifer talks about the potential use of 5-hydroxymethylcytosine profiling in the cancer clinic and the importance of this base in liquid biopsies for tumor detection. Pfeifer also explains the importance of studying aberrant DNA methylation patterns in ex-smokers.

“Aberrant methylation might then be providing a fertile ground for cancer driving mutations … So, if you bring the epigenome environment back to normal when you stop smoking, then this might be helpful in preventing the emergence of truly cancer driving events”, Pfeifer suggests.

Ajay Goel highlights his achievements and recent work in his interview ‘The era of biomarkers and precision medicine in colorectal cancer’, describing the non-invasive blood test for early detection of colorectal cancer as one of his proudest career moments [10].

Goel emphasizes the need for sequencing in genomic-based precision oncology but also raises issues such as cost that are holding precision medicine back.

“The data clearly show that if we were to sequence everybody and get a better sense of what their genomic makeup looks like, we would make more prudent therapeutic decisions compared to assuming everybody’s profile”, Goel claims.

Additionally, Goel speaks about the integration of miRNA biomarkers into the clinic: “The only challenge is specificity. And if you can address that, we will hit the home run we are looking for”. Goel also puts emphasis on the struggles of big data in biomarker research: “Big data is like a planetary system; you have a lot of stars but recognizing the true data set you want to use is a challenge”.

In the interview ‘Risks and rewards of big-data in epigenomics research’, Melanie Ehrlich also delves into the impacts of bioinformatics and big-data on her research [11].

“Epigenomes, transcriptomes and other big-data biology databases, especially those for humans, have provided me and myriad other biologists with tools that bring depth and breadth to genetic/epigenetic research and were unforeseen at the beginning of my scientific career”, Ehrlich explains.

Ehrlich gives an in-depth narration of the advantages and challenges of using epigenomic databases in research.

“One of the major applications of epigenomic and transcriptomic databases is to elucidate the regulation and function of a given human gene of interest for research or clinical purposes … The results from our studies demonstrate how very informative it is to focus on individual genes and their neighborhoods at epigenomic databases to find exceptions to and nuances of genome-wide trends in epigenetic/transcription associations not revealed by the overall genomic trends”, Ehrlich justifies.

“To avoid misleading conclusions from bioinformatic analysis of the above-mentioned databases, tissue heterogeneity, the age and gender of the tissue donors, and the appropriate choice of normal tissue to be compared to diseased tissue need to be carefully considered, as in all human epigenetic or transcription studies”, Ehrlich warns.

Finally, Jörg Tost provides an overview of his work to date and reflects on the progression of epigenomics research in his interview ‘Epigenomic technologies’ [12].

Tost delves into how we can best manage and utilize big datasets, highlighting issues of availability, reproducibility, and documentation on how tools and parameters are used.

“We should raise the bar on the quality of re-analysis, notably ICGC/TCGA data, to really question the novelty of the study. I think just an analysis of DNA methylation or microRNAs will not be sufficient to answer biomarker questions, so we have to be able to integrate, microRNA, genetic, epigenetic and metabolomic data”, Tost asserts.

Tost proposes solutions to better integrate epigenetics into the wider research community to generate more reliable data: “I think in general, the idea of including epigenetics in clinical trials, which are gathering data on multiple molecular levels to evaluate the efficiency of a treatment including epigenetic modifications on different levels is crucial”.

Tost highlights the challenges of specificity related to DNA-methylation-based biomarkers as well as practical hurdles in moving these technologies from research-oriented clinics to routine clinical laboratories.

“Perhaps, we need to be less dogmatic and stop thinking of diagnostic technologies solely as one test, but more of a combination of transcriptomic, proteomic and epigenetic data, including perhaps also the microbiome”, Tost suggests.

Overall, the members of the Epigenomics editorial board have all made significant contributions and discoveries to further our understanding of epigenomics. Reoccurring themes across the interviews include the persistent segregation of epigenetics from other fields, highlighting that the exclusion that epigenomics research first faced in its infancy still somewhat persists today. The researchers hold a magnifying lens to obstacles in epigenetic research – of which the overwhelming solution appears to be encouraging more cooperation between teams and across specialties – and collaboration is the key.

Financial&competing interests disclosure

Storm Johnson is an employee of Future Medicine Ltd, part of Future Science Group. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

Storm Johnson is an employee of Future Medicine Ltd, part of Future Science Group. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.