Società Italiana di Biofisica e Biologia Molecolare

 

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Premio Chiara D’Onofrio “Giovani” • 2015

Valentina Speranzini

Appassionata di viaggi e fotografia, Valentina Speranzini lavora all’Università di Pavia come assegnista di ricerca dove si occupa di epigenetica e biologia strutturale. Originaria di Cremona, si laurea nel 2010 a Parma in Biologia Molecolare sotto la supervisione del Prof. Riccardo Percudani, con una tesi di biochimica incentrata sull’analisi dell’origine molecolare dell’iperuricemia nell’uomo e nei primati antropomorfi. Dopo alcuni tirocini formativi, nel 2011 si trasferisce poi a Pavia, dove consegue il dottorato di ricerca in Scienze Biomolecolari e Biotecnologie nel laboratorio di Biologia Strutturale del Prof. Andrea Mattevi. Svolge parte della sua attività in Olanda, presso il Netherlands Cancer Institute di Amsterdam, grazie ad una borsa EMBO. Questo le permette di completare i suoi studi sui meccanismi molecolari di riconoscimento dei nucleosomi da parte del complesso modificatore della cromatina LSD1-CoREST. Nel 2014, dopo il dottorato, rimane a Pavia per ampliare gli studi di biochimica e biologia strutturale applicata all’epigenetica, focalizzandosi anche sul modificatore HDAC e sullo screening di potenziali inibitori di questo sistema.

Abstract
Mechanisms of nucleosome recognition by histone demethylase complex LSD1-CoREST

Human LSD1, Lysine-specific demethylase working on histone tail as chromatin modifier, is typically found in association with CoREST1 and HDACs, forming a stable module which acts in concert removing epigenetic marks for gene activation. LSD1 is involved in a large number of physiological processes, from gene silencing to differentiation, as well as many pathological events. Despite many biochemical data are available, the molecular bases for the substrate recognition by LSD1-CoREST1 (LC) are not known. Indeed, the aim of this research is to reveal the molecular details of the assembly of LSD1-CoREST1 in complex with the nucleosome (NCP). In this regard, the LSD1-CoREST1 heterodimer and its surface mutants have been purified in recombinant form, with the aim of mapping the enzyme-nucleosome interactions. We devised and reconstituted chemically-modified NCPs that proved to covalently stabilize the LC-NCP complex in vitro. This allowed, for the first time, the purification of a homogenous sample used for the research. The data obtained from fluorescence polarization and analytical chromatography were combined to build a starting model for the recognition process, that was fully dissected after we solved, in solution, the structure at low resolution of the complex using SAXS. These results allowed us to understand how the recognition of NCPs occurs: the nucleosome is initially engaged by CoREST1 binding to the DNA and this leads the histone tails to be detached from the NCP surface and subsequently being recognized and processed by the demethylase. Some questions still remain unsolved regarding the dynamics of the process, that is being analyzed through advanced microscopy techniques. Furthermore, our studies will involve histone deacetylase, a key player in the chromatin modification by LSD1.