Unraveling the biological function of chromatin associated proteins with mass spectrometry

October 18th 2018
Versione stampabile

Venue: Edificio Povo 2, via Sommarive nr. 9, Povo (Tn) - Room B105
 At 3.00 p.m.

  • Simone Sidoli - University of Pennsylvania, Perelman School of Medicine

Histones are the most abundant protein family in eukaryotic cells as, together with DNA, they define the structure and composition of chromatin. Histone post-translational modifications (PTMs) are covalent chemical groups capable of modeling chromatin accessibility, mostly due to their ability in recruiting enzymes responsible for DNA readout and remodeling. Histone PTMs are center of attention in developmental biology and medicine, as they are tightly linked to transcriptional regulation and epigenetics inheritance. Mutations in enzymes that are involved in catalyzing, removing or simply “reading” histone PTMs have been found in more than 50% of human cancers, and abnormal levels of histone PTMs are detected in diseases such as diabetes, PTSD, schizophrenia, allergies and addiction to name a few. Understanding the mechanism of chromatin regulators and developing drugs for therapy is therefore a field in exponential growth. In fact, many biotech and pharma companies are now equipped with an Epigenetics Division.

To date, we have identified more than 400 histone PTMs. Basically, histones can be modified with almost any type of PTM known to be on proteins. Moreover, these marks are often present in combinatorial patterns, making the understanding of their biological function very challenging. Today, we are confident about the role of about 10-15 histone PTMs, as the functional characterization of a single histone mark is a slow and complex process. Mass spectrometry (MS) has risen as the most accurate and fast methodology for large-scale characterization of protein PTMs. My scientific career has focused in establishing methods that allow confident identification and quantification of histone marks, plus an all new layer of quantification aspects that assist the functional determination of such PTMs. This includes labeling techniques to assess the accessibility of these marks on chromatin, identification of their readers, and defining in which order combinatorial marks are deposited on the chromatin, i.e. which are the potential drivers of epigenetics inheritance. We are now using these techniques to understand the mechanisms driving the development of diseases where the causative role of epigenetics aberrations is still poorly characterized.