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Discussing Diabetes & Epigenetics with Dr. Jean-Sébastien Annicotte

April 11, 2019

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Type 2 diabetes is a chronic metabolic disease that affects almost 400 million people worldwide, which is >8% of the global population. Type 2 diabetes is the most common form of diabetes and is caused by the failure of β-cells in the pancreas and insulin resistance in peripheral tissue, and is characterized by high glucose levels in the blood.

Due to the high incidence rates of diabetes, it is of high interest to find a cure for this disease. The restoration of β-cell mass and function has become a field of intensive research to identify the next generation of anti-diabetic drugs. Tremendous efforts have been made on deciphering epigenetic regulations that control metabolic tissue function.

Dr. Jean-Sébastien Annicotte On the Role of Epigenetics in Diabetes & Obesity

We recently caught up with Dr. Jean-Sébastien Annicotte, the group leader of the "Molecular Basis and Modelization of Diabetes and Obesity" team 2 at the French National Research Center in Lille.

Dr. Annicotte and researchers in his lab have been working on dissecting the molecular links between insulin-producing cells, insulin target tissues, type 2 diabetes, and obesity development. Their research has been focused on the role of cell cycle regulators and their transcriptional co-regulators in the control of metabolic homeostasis, and their role in type 2 diabetes and obesity.

Listen to the full interview with Dr. Jean-Sébastien Annicotte on Active Motif’s Epigenetics Podcast.

Stefan Dillinger: A question I like to ask every guest to start off our podcast is how did you become interested in pursuing a career in science, or at least in basic biology?

Dr. Jean-Sébastien Annicotte: During my Ph.D., I was supervised by Johan Auwerx and Kristina Schoonjans, who were world leaders in the field of metabolic research and gene regulation. They gave me a really nice opportunity to start my scientific career in the best environment that a Ph.D. student could dream of. In particular, my project was highly risky but they gave me all the keys to be successful. And working with the team was highly motivating, challenging, and stimulating. I think science is really exciting, and I feel my work has passion. What could be better than doing this all my life? Nothing I guess.

Stefan: Was there a key situation that you had in your childhood that interested you in biology?

JSA: Yeah, actually it was during my studies, I had a professor that taught me about mitosis and I thought it was really interesting and exciting. So I said okay this is probably something I would like to do in my career.

What is Diabetes, and What are the Differences Between Type 1 and Type 2?

Stefan: Your main research focus is on diabetes, and specifically type 2 diabetes. Could you give us a quick overview of type 2 diabetes and what differentiates it from type 1 diabetes?

JSA: Diabetes mellitus is a chronic disease caused by the limited production of insulin by the pancreas or by the ineffectiveness of the insulin produced. Such a deficiency results in increased concentrations of glucose in the blood, which in turn damages many of the body systems, in particular, the blood vessels and nerves.

There are two principal forms of diabetes. Type 1 diabetes, in which the pancreas fails to produce insulin, which is essential for survival, and type 2 diabetes, which results from the body’s inability to respond properly to the action of insulin produced by the pancreas.

Type 2 diabetes is much more common and accounts for around 80-90 percent of all diabetes cases worldwide. Type 2 diabetes occurs most frequently in adulthood but is being noted increasingly in adolescence as well.

What is the Link Between Epigenetics & Diabetes?

Stefan: How does epigenetics come into play into this disease, and which epigenetic factors might play a role in this?

JSA: There are several ways to control gene expression, in particular, the subtle and reversible modification on DNA and histones plays a key role in transcription and subsequent adaptation to the cell to its environment. Certain genetic markers have been shown to increase the risk of developing type 1 and type 2 diabetes. In addition, several environmental factors may impact the risk of developing diabetes.

At the beginning of my career this was not obvious, but several important studies have shown that modification of histones could turn on or off the expression of genes and directly impact the function of a cell. After working for years on studying the contribution of transcription factors, it appeared interesting to add this new layer of complexity to our studies and try to better understand the mode of action, so epigenetics entered the game.

Investigating the Molecular Mechanisms Behind Diabetes

Stefan: When looking into the research in your lab, the first thing I came across was LRH1. It seems that your main goal here was to decode the role of transcription factors and transcription co-regulators in diabetes. In order to investigate its role in the disease you created a mouse model for the conditional inactivation of the orphan nuclear receptor LRH1. Why did you focus on this target, and what kind of results did you obtain using your mouse model system?

JSA: This was one of the main subjects of my lab in Strasbourg, so at that time, this nuclear receptor was a hot topic. It was cloned a few years ago, but its function was unknown. Tools were not available to decipher its functions, so the best strategy was to develop a mouse model in which we could remove the gene in a tissue- and time-specific manner. I spent more than four years creating this model, and this helped us to understand its contribution to liver diseases, inflammation, as well as cancer.

Stefan: What were the main challenges you faced in creating this mouse model system?

JSA: At that time, it was not too complicated to manipulate DNA, but I realized that it was not easy to screen cells for the presence of the mutations. I did a lot of ES cell screening to obtain this mutation, and it was really a nightmare because we had two ES cell clones, but it was really hard to obtain the mice because there was a hypomorphic allele which made it really, really tough to obtain the mice.

Stefan: So, then finally you got your mice, what kind of regulatory pathways did you then unravel?

JSA: We did find several pathways that were regulated by this nuclear receptor, at the chromatin level including glucocorticoid synthesis, inflammation, and adrenoreceptor signaling in cancers. And during my Ph.D. I developed chromatin IPs using mouse tissues, and it was not easy at that time. I finally succeeded and this really reinforced the importance of better understanding what was happening at the chromatin level.

Stefan: Then you moved on and in a paper published in 2009 in Nature Cell Biology, you discovered that the transcription factor E2F1 was a key regulator of pancreatic β-cell proliferation and function, could you briefly describe the role of E2F1 and insulin secretion?

JSA: Actually during my Ph.D. I also worked on E2F1. We published a paper where we demonstrated that the cell cycle regulator E2F1, a transcription factor which was previously known to control cell proliferation, also regulated postnatal pancreatic β-cell proliferation. We later showed that E2F1 also controls insulin secretion for the regulation of key target genes and β-cells. And once again chromatin regulation was key in this new layer of regulation.

Stefan: In a later study with your E2F1 knockout mice, you investigated the role of E2F1 in oxidative metabolism. What did you find, what was the role of E2F1?

JSA: We demonstrated that E2F1 forms a complex on its target genes with the retinoblastoma tumor repressor protein, and that in its absence, such as observed in the knockout mice, genes are derepressed leading to the activation a specific gene expression program that is involved in oxidative metabolism and mitochondrial functions.

Stefan: Last year you published a paper investigating the effect of E2F1 in gluconeogenesis, and the effects on diabetes, right?

JSA: This is the most recent of our discoveries to date. We showed in this study that removing E2F1 protects against nonalcoholic steatohepatitis, often associated with insulin resistance and tied to diabetes. In addition, we also demonstrated that it controls hepatic glucose production, one of the hallmarks of type 2 diabetes.

Stefan: Something very interesting that you studied more recently is KAT2B, which is a histone acetyltransferase. You published on this in 2016 in a Cell Reports paper. You made knockout mice here too, how did the loss of this enzyme influence your mice?

JSA: The link between KAT2B and E2F1 has been demonstrated in the past, so following our studies in the liver and pancreas I was really looking for a chromatin remodeling complex that could explain the paradoxical role of E2F1 in the pancreas at the same time controlling insulin secretion, which decreases glycemia, and also in the liver controlling glucose production. So to me, the only explanation could be related to the E2F1 interactome. We started by studying the role of KAT2B, which has been shown to be a partner of E2F1 and demonstrated it directly regulates insulin secretion.

Stefan: Did you also have a look at whether histone modifications were altered in the KAT2B knockout mice?

JSA: Not initially because those types of experiments with pancreatic tissue were complicated. But we are now currently evaluating the distribution of some histone marks in a genome-wide manner to identify the contribution of KAT2B to modify the epigenetic code in different settings, including diabetes.

How Does RNA Methylation Contribute to Diabetes?

Stefan: You are also currently investigating epitranscriptomics (RNA methylation) in your lab, which is obviously a very hot topic at the moment. Since this research is all unpublished I don't want to go into too much detail but could you just tell me a little bit more about what you are doing in this area?

JSA: What we and others have observed is that it’s not only DNA or histones that could have epigenetic modifications. There was an old process that was discovered in the 1970s that was the modification of RNA. RNA can also be methylated like DNA and what is really important and interesting is there's quite a lot of regulation linked to methylation of RNAs, such as stability of the RNA, translation, and stuff like that.

We are pretty sure that this is really important in metabolic diseases and could contribute to diseases like diabetes. I won’t talk too much about that because we are investigating this effect, but we are pretty sure that there's a new layer of regulation that is linked to RNA modifications and epitranscriptomics.

Stefan: This is really interesting because we now have three layers of regulation, with the primary sequence of the DNA, then you have the epigenetics, which is histone code and DNA methylation, and now there is another layer coming into the game with RNA methylation and other RNA modifications. This is really getting complex!

JSA: Yeah, and actually I think that all are linked together, so that means that you need to have some histone modification to have RNA methylation. There are some really nice papers coming out now, like a Nature paper showing that there is a direct link between H3K46me3 and methylation of RNA so, this is a really hot topic now.

Drugs & Therapeutic Options for Diabetes

Stefan: If you take all this together now, your studies and things from the literature, what kinds of therapeutic strategies do you see emerging to treat diabetes?

JSA: This is a really tricky question. I think that some molecules are currently on the market, but it remains difficult to maintain a controlled glycemic profile for diabetic patients. Therefore, we need new drugs to treat diabetes, I hope we will make some progress in that direction based on our past and future results.

Stefan: What do you think will be the most important drug targets, is it more the enzymes?

JSA: This is exactly what we are currently looking into now. We have some targets that we have identified, and we are testing molecules to modify the action of these targets. We are also analyzing whether those drugs that are targeting our specific proteins and enzymes impact type 2 diabetes development in pre-clinical models.

What’s Next for the Future of Diabetes?

Stefan: Where do you think the field of diabetes research is moving, especially in terms of epigenetics?

JSA: Epigenetics is a really hot topic and several studies demonstrate that mechanisms regulating type 2 diabetes are epigenetically controlled. We need to be really precise in deciphering the exact mechanisms that are involved in these diseases, and I'm pretty sure we will learn a lot in the near future with the development of new technologies such as RIME (ChIP followed by mass spec instead of NGS) and single-cell analyses, for example. So there's still a lot of work to do, but we'll continue to work on it with patience.

Stefan: What do you think will be the bottlenecks here? There are several new techniques coming out, like RNA-Seq and MeDIP-Seq for RNA. Where do you see the limitations, or where do see that improvements need to be made?

JSA: I think there's a limitation in our human resources because you need a lot of people to do these types of experiments, and you need also to have some computational biology to analyze all the data that is now generated by these types of approaches. Once you have all these human resources and computational biologists, bioinformatical biologists also, then you can think about analyzing the data and go in a good direction.

Stefan: Do you think that machine learning and artificial intelligence will help going forward?

JSA: It will, I'm pretty sure it will. I don't know how yet, but this is something that we are thinking about.

Stefan: Jean-Sébastien, thank you very much for your time and for the interview. We wish you continued success and look forward to seeing what you and your group publish next!

Listen to the full interview with Dr. Jean-Sébastien Annicotte on Active Motif’s Epigenetics Podcast.

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