Our group develops and utilizes biochemical methods to identify molecular mechanisms of chromatin decondensation during aging. To do so, we innovate biological models based on 3D cell cultures (we are the CelVivo US Center of Excellence), optimize methods using mass spectrometry, and establish innovative sample collecting methods such as breath condensation to develop non-invasive biopsies. The Sidoli lab is part of the (i) Einstein Comprehensive Cancer Center, (ii) the Nathan Shock Center on Biology of Aging Research, (iii) the ERC-CFAR Einstein-Rockefeller-CUNY Center for AIDS research, (iv) the Einstein Institute of Neuroimmunology and Inflammation, and (v) the Einstein Institute for Immunotherapy of Cancer.

Figure below adapted from a review of Dr. Andrew Feinberg (NEJM, 2018)

Career path of the Principal Investigator, Dr. Simone Sidoli

Simone approached mass spectrometry (MS) as a trainee at the Department of Chemistry of the University of Parma (Italy). There, he established methods to detect allergens in aliments, as food and food safety are critical aspects of the economy of his hometown. Next, he chose a PhD program at the University of Southern Denmark (Odense, DK) in Dr. Ole Jensen lab, where he developed methods for protein analysis, processing large datasets and learned to maintain state-of-the-art instrumentation. There, he published my first papers on the analysis of combinatorial histone post-translational modifications (PTMs) and cell signaling, i.e. phosphoproteomics. His MS method to analyze co-existing histone PTMs is currently the most accurate and sensitive in literature. In 2014, Simone joined the laboratory of Dr. Benjamin Garcia’s lab at the Epigenetics Institute of the University of Pennsylvania (Philadelphia, PA, USA) for my postdoc. There, he investigated aberrant systems like cancer cells by developing a proteomics and computational pipeline to link cell signaling cascades (protein phosphorylation) with chromatin changes (histone modifications). With the methods he developed at UPenn it is now possible to define the turnover of protein PTMs to e.g. determine the order of deposition of PTMs on histone tails. Furthermore, Simone developed technology to (i) investigate protein-RNA interactions, (ii) identify and quantify unexplored protein modifications such as isobaric phosphorylations, and (iii) alternative workflows to deeply characterize the cell metabolome. After these experiences, he joined the Department of Biochemistry at the Albert Einstein College of Medicine as tenure-track assistant professor in 2019.

Current research goals

We have focused our technology on solving state and dynamics of chromatin. Specifically, in our team we aim to identify which molecular mechanisms regulate the compaction state of chromatin when cells undergo biological stress like aging, but also uncontrolled cell proliferation (cancer) and pathogen infection. The role of chromatin during aging has been under the spotlight, e.g. DNA methylation is used as biological clock and stochastic DNA mutations accumulate during our lifespan. However, it remains unclear which proteins control the equilibrium that maintains proper chromatin compaction, and which histone modifications recruit those proteins. If we could identify mechanisms of “protection” of chromatin, we might be able to delay or even arrest the aging process. Our lab approaches this research program by addressing these specific questions: (i) which proteins occupy chromatin domains that anomalously decondense? (ii) Are there specific histone codes that label these domains? (iii) How heterogeneous is anomalous chromatin decondensation in apparently homogeneous cell populations? (iv) How gerotherapeutics affect DNA readout? As they affect cell metabolism, are certain metabolites converted into chromatin modifications? (v) Can we modify our diet with supplements that aid metabolites for chromatin protection?

Currently, our team has made tremendous progress towards identifying new histone modifications that decorate chromatin of individuals with exceptional longevity (LonGenity program). Together with the Nathan Shock Center of Excellence at Einstein, we have studied chromatin in T- and B-cells of centenarians and their progeny, and identified histone succinylation as potential link between metabolism, chromatin protection and mechanism of gerotherapeutics. Histone succinylation derives from succinic acid, a TCA intermediate processed after alpha-ketoglutarate (known gerotherapeutic). We discovered that histone succinylation binds to specific chromatin readers differently than acetylation, and we demonstrated that histone succinylation accumulates in cells treated with metformin and rapamycin (also gerotherapeutics). We are currently investigating the biochemistry of this modification, as well as a diet with succinic acid in model organisms.

In parallel, we have models in our lab of anomalous chromatin decondensation. Mostly, we create these models with 3D cell culture in a zero-gravity environment, which ensures long-term cell quiescence without cell death. This is critical to study chromatin state zeroing out the effect of the cell cycle, as well as modeling a metabolism more closely related to cells into our body compared to highly proliferating cell cultures. Other members of the lab investigate these models by optimizing the analysis of combinatorial histone codes with “middle-down” mass spectrometry, optimizing the acquisition and the data analysis of histone modifications at single cell levels, and characterizing the biological function of proteins reading “hybrid” histone modifications, i.e. histone tails modified with markers of repressive heterochromatin but co-modified with acetylations depicting accessibility. Furthermore, we have worked on methods to study proteomes at single genomic loci and accurately map protein-ligand interactions at single amino acid resolution. Altogether, the Sidoli lab works on a research program where we aim to define how the proteome interacts with chromatin anomalous decondensation and how to prevent these anomalies for a healthier cellular aging.

We develop innovative technology mainly based on mass spectrometry to identify the proteins that recognize those decondensing chromatin domains. Our lab utilizes proteomics approaches as well as other methods to quantify small molecules such as DNA modifications. We invest in methods to enhance the throughput and the robustness of the analysis to bridge the gap into translational science (diagnostics). We have also an exciting partnership with Medivac (Parma, Italy) to optimize minimally invasive biopsies through condensing patients’ breath.

To model more accurately chromatin dynamics in cell culture, we have introduced in our lab in collaboration with CelVivo IVS (Odense, Denmark) an innovative incubator to grow 3D synthetic tissues in a cell lab preventing the issue of unnatural rapid DNA replication typical of cell cultures. Overall, our research aims to improve the understanding (and potentially hypothesize treatment options) of the role of histone modifications in conditional chromatin decondensation.