EPIGENETICS,
METABOLISM AND AGING

Understanding epigenetics for healthy aging

Manlio Vinciguerra, Ph.D., MSc

Research focus
The research focus of the Epigenetics in Metabolism and Aging team consists of 3 research lines. The major research interest is to understand how histone variants, an exquisite epigenetic mechanism of regulation of gene expression in mammals, affects cell metabolism, reprograming and cancer. The EMA studies how large histone variants called macroH2A1.1 and macroH2A1.2, splicing isoforms of macroH2A1, function as energy sensors and oncogenes in many cancer types and during induced pluripotent stem cells reprograming. The second line of investigation concerns the study of new-patented senolytics, drugs that kill selectively senescent cells in liver physiology and pathology. The third line of investigation involves the detailed study of the role of a rejuvenating factor, identified through parabiotic screening called Growth Differentiation Factor 11 (GDF11) in nutrient metabolism in mice.

Research objectives

• Study the epigenetic macroH2A1 isoforms and DNA-damage components of endothelial cells repro­graming into induced pluripotent stem cells (iPSC).

• Identification of the central and systemic effects of senolytics (dasatinib+guercetin, and a new-patented one) in mice.

• Uncovering the side effects of the „youth factor“ GDF11 in obese mice and humans.

Main partners

• University College London, London, UK

• University of Southern California, Los Angeles, USA

• University of Barcelona, Barcelona, Spain

Top publications

  • VINCIGUERRA, M., SGROI, A., VEYRAT-DUREBEX, C., RUBBIA-BRANDT, L., BUHLER, L.H., FOTI, M. Unsaturated fatty acids inhibit the expression of tumor suppressor PTEN (phosphatase and tensin homolog) via microRNA-21 upregulation in hepatocytes. Hepatology. 2009, 49(4), 1176-1184.
  • PLANAVILA, A., REDONDO, I., HONDARES, E., VINCIGUERRA, M., MUNTS, C., IGLESIAS, R., GABRIELLI, L., SITGES, M., GIRALT, M., VAN BILSEN, M., VILLARROYA, F. Fibroblast growth factor-21 exerts a protective role against cardiac hypertrophy. Nature Communications. 2013, 4, 2019.
  • SHEEDFAR, F., VERMEER, M., PAZIENZA, V., VILLARROYA, J., RAPPA, F., CAPPELLO, F., VILLARROYA, F., VAN DER MOLEN, H., HOFKER, M., KOONEN, D., VINCIGUERRA, M. Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high fat diet. International Journal of Obesity. 2014, 39(2), 331-338.
  • BRANDHORST, S., CHOI, I., CHENG, C.W., WEI, M., SEDRAKYAN, S., NAVARRE, G., DUBEAU, L., PENG YAP, L., PARK, R., VINCIGUERRA, M., DI BIASE, S., MIRZAEI, H., CHILDRESS, P., JI, L., GROSHEN, S., PENNA, F., ODETTI, P., PERIN, L., CONTI, P.S., IKENO, Y., KENNEDY, B.K., COHEN, P., MORGAN, T.E., LONGO, V.D. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metabolism. 2015, 22(1), 86-99.
  • BORGHESAN, M., FUSILLI, C., RAPPA, F., PANEBIANCO, C., RIZZO, G., OBEN, J.A., MAZZOCCOLI, G., FAULKES, C., PATA, I., AGODI, A., REZAEE, F., MINOGUE, S., WARREN, A., PETERSON, A., SEDIVY, J.M., DOUET, J., BUSCHBECK, M., CAPPELLO, F., MAZZA, T., PAZIENZA, V., VINCIGUERRA, M. DNA hypomethylation and histone variant macroH2A1 synergistically attenuate chemotherapy-induced senescence to promote hepatocellular carcinoma progression. Cancer Research. 2016, 76(3), 594-606.

Other selected results

HUVEC-derived iPSC overexpressing macroH2A1.1 isoform display more efficient reprogramming and higher levels of DNA damage repair (DDR). Recent results:

  • Identification of macroH2A1.1 and macroH2A1.2 binding partners by mass-spec, functional validation in IPSC.
  • RNA-Seq in iPSC overexpressing macroH2A1 isoforms.

Another line of investigation concerns the role of circulating histones, including macroH2A1 isoforms, as markers of disease. We have recently identified a new circulating histone signature able to discriminate the severity of steatosis in individuals with lean metabolic associated fatty liver disease (MAFLD).