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Silvia ZUCCHELLI: Research interests/expertises

Molecular mechanisms and therapeutic applications of SINEUPTM technology

We have recently discovered a new class of antisense (AS) lncRNAs, whose dominant effect is to promote translation of partially overlapping sense protein-coding mRNAs with no effects on RNA levels (Carrieri C., et al., Nature 2012). As these lncRNAs depend on an inverted SINEB2 repetitive element for induction of protein synthesis, we named these molecules SINEUPTM. SINEUPTM activity depends on two functional domains: 1) a 5’ sequence that overlaps with the coding mRNA in the opposite orientation and that confers target specificity (Binding Domain); 2) an embedded inverted SINEB2 element that functions as activator of translation (Effector Domain). We have previously demonstrated that by swapping binding domains, one can generate SINEUPTM molecules to target virtually any protein of interest. Importantly, the enhancement is within a more physiological range (2-3 fold) than obtained by other gene therapy strategies. These features render SINEUPTM technology of particular interest for therapeutic correction of aploinsufficiencies.

The aim of our research is to study the molecular mechanisms that control SINEUPTM activity within the cell and to generate synthetic SINEUPTM molecules to target therapeutic proteins and correct haplo-insufficiency defects in vivo.

 

Analysis of antisense transcription in loci associated to neurodegenerative diseases

The FANTOM5 sequencing datasets represent the largest collection of transcriptomes from human cell lines, primary cells and whole tissues of various origins. Transcription starting sites are mapped at high resolution by the use of a modified protocol of Cap-Analysis of Gene Expression (CAGE) for high-throughput single molecule next-generation sequencing with Helicos (hCAGE). As part of the FANTOM5 consortium, we were able to dissect the Promoterome associated to cellular and tissue functions in the body (Forrest A.R.R., et al., submitted).

We interrogated a total of 66 tissue- and 244 cell-specific libraries for the presence of antisense transcription to well-established loci associated to Alzheimer’s disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Huntington’s and Parkinson’s disease. Antisense transcription was validated for a subset of genes, including amyloid precursor protein, microtubule-associated protein tau, DJ-1, leucin-rich repeat kinase 2 and a-synuclein (Zucchelli S., et al., FANTOM5 satellite manuscript, submitted).

Future studies will be focused on the functional role of newly identified antisense transcripts and their impact on neurodegeneration. This line of research is held in collaboration with the Laboratory of Functional Neurogenomics at SISSA (Trieste, Italy).

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