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Dissecting cytosine methylation mechanics of dysmetabolism

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  • Date: - -
  • Venue: Collegio A Volta, Pavia
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On the 31st of October 2019 Francesco Spallotta, Turin University, will give a seminar entitled Dissecting cytosine methylation mechanics of dysmetabolism at 2.00 pm in the College lecture theatre (Collegio A Volta).  All students are invited to attend, especially those reading Medicine, Biology, Biotechnology and Pharmaceutical Sciences. The poster of the lecture can be downloaded here.

Cytosine methylation harnesses chromatin plasticity and gene transcription affecting cell functions and fate. Recently an active biological role has been assigned to different stable cytosine iterative modifications enriched during DNA demethylation cycle including 5-hydroxy- and 5-formyl-cytosine. Metabolite availability directly regulates DNA (de)methylation enzymatic machinery, as the involved enzymes, DNA methyltransferases, Tet methylcytosine dioxygenases (TETs) and Thymine DNA Glycosylase (TDG), exploit S-Adenosyl methionine and α-ketoglutarate (αKG) to exert their activity. Consequently, metabolite availability can ultimately influence the levels of different cytosine modifications. In this light, in the tumor microenvironment, the balance between αKG and oncometabolites, including 2-hydroxyglutarate (2HG), succinate and fumarate, plays a crucial role in the regulation of DNA demethylation.
In first part of my talk, I will show how chronic metabolic derangement associated to type 2 diabetes and cancer affects intracellular balance between αKG and 2HG, thus altering DNA (de)methylation cycle. Specifically, we recently published that cardiac mesenchymal cells isolated from diabetic donors show reduced levels of αKG in comparison to the ones isolated from normoglycemic donors. The decreased availability of αKG associates to an altered cytosine methylation pattern consequence of a compromised TET/TDG association and function with TET1 relocation out of the nucleus.
In the second part of the talk, I will show preliminary data about the effect of chronic dysmetabolism, achieved by high-fat diet, on a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC). Specifically, I will show the impact of dysmetabolism on the αKG/oncometabolite balance and the cytosine modification levels. Moreover, the effect of oncometabolite enrichment on pancreatic stellate cells and cancer associated fibroblasts isolated from pancreas of PDAC patients will be discussed.
Lastly, the efficacy of epi-metabolic compounds, aimed at restoring the epi-metabolic control of DNA methylation cycle, will be showed in rescuing type 2 diabetes-dependent cardiac features and in preventing breast cancer associated lung metastasis. Specifically, the novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of αKG dehydrogenase, increased the αKG level in diabetic cardiac mesenchymal cells and in the heart of hyperglycemic mouse models eliciting DNA demethylation, glucose uptake, and insulin response. The same compound was tested in an orthotopic mouse model of breast cancer. Also in this context, AA6 altered Krebs cycle causing intracellular αKG accumulation and, consequently, the activity of TETs was restored. In mice, AA6 injection reduced metastasis formation and increased 5hmC levels in primary tumours. This epigenetically remodelled metabolic environment efficiently counteracted the initiating steps of tumour invasion inhibiting the epithelial-to-mesenchymal transition (EMT).

Spallotta F et al., Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients: Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation. Circ Res. 2018 Jan 5;122(1):31-46.

Atlante S et al., α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis. Cell Death Dis. 2018 Jul 9;9(7):756.

Kohli RM et al., TET enzymes, TDG and the dynamics of DNA demethylation. Nature 2013;502:472-9.

F. Spallotta is a senior research fellow at Department of Oncology, Turin University (Turin-Italy) located at Candiolo Cancer Institute FPO-IRCCS. From 2005 to 2010 he was Master of Science student and PhD student at the Vascular Pathology Laboratory of the “Istituto Dermopatico dell’Immacolata-IRCCS” (Rome-Italy). From 2010 to 2012 he accomplished his PhD in Experimental Medicine and started his postdoctoral training at the Vascular Biology and Regenerative Medicine Laboratory of the “Centro Cardiologico Monzino-IRCCS” (Milan-Italy). From 2012 to 2018 he was one of the former postdoctoral fellow at the Division of Cardiovascular Epigenetics at Goethe University (Frankfurt am Main-Germany). Moving from one lab to another was extremely stimulating and enriched his background, giving him the opportunity to contribute to several research projects.
Dr Spallotta has a strong expertise in cellular and molecular biology and he is extremely proficient with many cellular and in vivo models suitable to study different physio-pathological context. Since 2005, he worked in the field of epigenetics pointing out novel molecular mechanisms underpinning onset and progression of different human diseases. Since 2014, he started to explore the link between epigenetics and metabolism, especially in response to dysmetabolic contexts associated with diabetes, aging and cancer and established following specific dietary regimens, including high fat diet, fast mimicking diet and ketogenic diet. Recently he elucidated an altered DNA methylation pattern associated with reduced level of α-ketoglutarate in mesenchymal cardiac cells isolated from type-2 diabetic patients pointing out a mechanism at the molecular base of the so called “hyperglycemic memory” responsible for cardiovascular complications in diabetes. Moreover, he characterized the contribution of the same metabolite, α-ketoglutarate, during breast cancer-associated lung metastasis. At present he is investigating the link between colorectal cancer and pancreatic ductal adenocarcinoma with diabetes and obesity. In all his studies he applied integrative OMICS analysis by performing DNA methylome sequencing, ChIP-sequencing, RNA-sequencing and metabolome analysis.

Murine pancreas, SPIM (Jürgen Mayer, Centre de Regulació Genòmica & Universitat Pompeu Fabra)

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