Since 2012, Dr Marzi has been working "non-coding Genome" laboratory, headed by Dr. Francesco Nicassio, now coordinator of the Center for Genomic Science at IIT@SEMM in Milan.
With a Master Degree in Pharmaceutical Biotechnology and a PhD in Molecular Medicine, the scientific career of Dr.Marzi has been characterised by a general interest in the role of non-coding RNAs (microRNAs, lncRNAs) and their ability to modify the expression of genes, shaping cell fate (Marzi et al. J Cell Biol 2012). To this purpose, he acquired familiarity with both computational and experimental approaches, exploiting several genome-wide approaches (small RNA-seq, RNA-seq, ATAC-seq, ChIP-seq), novel technologies and bioinformatics to dissect regulatory gene networks involved in cell differentiation, stem cell biology and cancer (Muller, Marzi et al., Front. Bioeng. Biotechnol. 2014; Marzi et al. Clinical Chemistry 2016). Furthermore, Dr. Marzi contributed to establish in the last few years fruitful collaborations with other laboratories, developing additional lines of research including the analysis of the transcriptional programs governing the development and differentiation of the central nervous system.
Contributing more than ten publications in high impact journals and an international patent on "Cancer Biomarkers" and their clinical use (Bianchi et al. EMBO Mol Med 2011), Dr. Marzi developed within the noncoding Genome lab at IIT two mail lines of research (see Project section):
- miRNA Degradation Mechanisms and their interplay with RNA Targets
- Non-coding elements in epigenetic and transcriptional plasticity
- ROCHE funded project
- 2011 “Phd in Molecular Medicine” (4 years degree at the European School of Molecular Medicine, within the IFOM-IEO-CAMPUS)
- 2006: “Laurea magistrale in Biotecnologie Farmaceutiche” (5 years degree; final mark 110 cum laude) at the University of Milan
- 2000: “Diploma di maturita’ scientifica” (High School; final mark 99/100) at Liceo Scientifico Leonardo da Vinci, Milan
- 2012-to present: Post-doctoral Fellowship at Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT)
- 2010-2012: Post-doctoral Fellowship at the Molecular Medicine Program, European Institute of Oncology (IEO).
- 2007-2010: PhD studentship in Molecular Medicine (European School of Molecular Medicine, SEMM) at IFOM-IEO campus, Pier Paolo Di Fiore’s group.
- 2005-2006: Research training for Biotechnology Degree at the Centre of Excellence for Neurodegenerative Diseases (CEND), University of Milano,Adriana Maggi's lab.
miRNA Degradation Mechanisms and their interplay with RNA Targets
MicroRNAs are small molecules that regulate negatively gene expression, by promoting the degradation of their targets. Thus, it is not surprising that micoRNAs play a crucial role in several physiological and pathological contexts, including cancer biology. The alteration of the normal expression level of microRNAs (i.e. over- or under-expression) leads to aberrant expression of the targets and, for this reason, several mechanisms evolved to maintain the correct homeostasis of microRNAs. Recently, our lab and others discovered a new mechanism controlling microRNAs degradation, which was named Target-Dependent miRNA degradation (TDMD). TDMD is a process by which some peculaliar targets, showing special features in terms of binding (i.e. a stronger compared to canonical targets), are able not only to elude the control of their cognate microRNA but also to promote the degradation of microRNAs. In other words, the TDMD mechanism reduce the intracellular levels and activity of some microRNAs.
Our lab is currently investigating the involvement of TDMD transcripts in human disease, with an emphasis on cancer, with the aim of defining the role played by TDMD transcripts in modulating miRNA functions (CARIPLO funded project) and the possible clinical applications of TDMD in human tumors.
MicroRNAs (miRNAs) are a class of small non-coding RNAs that function as guide molecules in RNA silencing. The miRNA:target interaction usually occurs at the 5′ end of the miRNA (the ‘seed’ region). In the last few years, it has emerged that there is a special class of targets which bind the miRNA not only through the seed, but also through a second region of complementarity at the 3′ end of the miRNA. The extended complementarity forces the miRNA out of Ago2, where it becomes accessible to enzymatic degradation.
Our lab was involved in the identification of one of the first endogenous target capable of triggering miRNA degradation (Ghini, Rubolino et al. Nat Commun 2018).However, we still miss how many of such transcripts could exist and the potential impact of TDMD mechanism in human cancer.
We are currently developing new bioinformatics pipelines, based on combined sequence alignment and feature selection approaches, to select for TDMD interactions in order to build a high confidence database that can be exploited to forster additional research lines and to isolate the best candidates that will be further investigated in order to unveal their clinical utility in the management of tumors.
Non-coding elements in epigenetic and transcriptional plasticity
Among the millions of cells constituting a tumor, there are often a few that can survive treatment and cause tumor relapse and metastatic dissemination. Through genetic events, such as mutations, and non-genetic (“epigenetic")mechanisms, these cells adapt to challenging environmental conditions and make the tumor progress. Current therapies, such as chemotherapy, are severely hindered by the difficulty dealing with these “adaptive responses”.
In our lab, we investigate the non-coding elements that contribute, both at RNA level (ncRNAs) and DNA level (“enhancers"), to shaping the "adaptive responses" that allow cancer cells to survive, disseminate and metastasize.
We predict that a targeted therapy based on these regulators should be successful in eradicating cancer cells surviving chemotherapy.
Epigenetic plasticity (i.e., transcriptional heterogeneity) has emerged as a new hallmark of cancer, as it can give cells the ability to adapt to challenging environmental conditions, such as cancer therapy or metastasis formation. At the mechanistic level, adaptation is regulated by the complex interplay between dynamic regulatory elements (such as enhancers) and their target genes, which ultimately determine the cell response. Unfortunately, only a tiny fraction of the hundreds of thousands of regulatory elements in our genome has been characterized.
With this project, we mainly aim to identify enhancer-gene and lncRNA-gene interactions that are functionally relevant for breast cancer adaptative processes.
So far, we have been focusing on triple-negative breast cancer, an aggressive tumor sub-type characterised by extensive heterogeneity and few therapeutic options. We have already developed several experimental models with high epigenetic plasticity and employed cutting-edge genomic approaches (including NET-Cage, single cell ATAC sequencing and Nanopore sequencing) to identify the regulatory elements (~600 lncRNAs and ~1000 enhancers) that are putatively involved in adaptive responses (e.g. response to chemotherapy, cancer stem cells).
We are currently investigating the functional and transcriptional impact of perturbing each of these regions. Our innovative strategy combines CRISPR interference with single cell RNA sequencing by assigning a unique transcribed barcode to each sgRNA. In this way, single-cell RNA-seq profiles can be used to investigate which cell programs are affected by each individual perturbation. With this approach, we want to identify the cis- and -trans regulatory networks that control cancer cells ability to adapt to therapy.
In the long term, our study will allow us to identify diagnostic targets and therapeutic markers and improve the patients' survival rate.
This project is supported by a ROCHE individual grant to Dr. Marzi.
Frataxin gene editing rescues Friedreich’s ataxia pathology in dorsal root ganglia organoid-derived sensory neuronsNature Communications, vol. 11, (no. 1)
Dual role for miR-34a in the control of early progenitor proliferation and commitment in the mammary gland and in breast cancerOncogene, vol. 38, (no. 3), pp. 360-374
LncRNA EPR controls epithelial proliferation by coordinating Cdkn1a transcription and mRNA decay response to TGF-βNature Communications, vol. 10, (no. 1)
miR-135a-5p is critical for exercise-induced adult neurogenesisStem Cell Reports
MiR-135a-5p Is Critical for Exercise-Induced Adult NeurogenesisStem Cell Reports, vol. 12, (no. 6), pp. 1298-1312
Endogenous transcripts control miRNA levels and activity in mammalian cells by target-directed miRNA degradationNature Communications, vol. 9, (no. 1)
Uncovering the stability of mature miRNAs by 4-thio-uridine metabolic labelingMethods in molecular biology (Clifton, N.J.), vol. 1823, pp. 141-152
Endogenous transcripts control miRNA levels and activity in mammalian cells by a target-induced miRNA degradation mechanism (TIMD)2nd International Conference on the Long and the Short of Non-Coding RNAs
Endogenous transcripts control miRNA levels and activity in mammalian cells by a target-induced miRNA degradation mechanism (TIMD)EMBO | EMBL Symposia :Non-coding Genome
Long non-coding RNAs (lncRNAs) and stem cells properties in breast cancerKeystone Symposia: Noncoding RNAs: From Disease to Targeted Therapeutics (J5)
MicroRNA-independent functions of DGCR8 are essential for neocortical development and TBR1 expressionEMBO Reports, vol. 18, (no. 4), pp. 603-618
Study of Target-Induced miRNA Degradation by CRISPR/Cas9 deletion of miRNA responsive elementsXVI CONGRESSO REGIONALE SISA-XI CONGRESSO NAZIONALE SITeCS
Synergic Functions of miRNAs Determine Neuronal Fate of Adult Neural Stem CellsStem Cell Reports, vol. 8, (no. 4), pp. 1046-1061
Degradation dynamics of micrornas revealed by a novel pulse-chase approachGenome Research, vol. 26, (no. 4), pp. 554-565
Optimization and standardization of circulating MicroRNA detection for clinical application: The miR-test caseClinical Chemistry, vol. 62, (no. 5), pp. 743-754
The plasticity of miRNA pool: a novel approach to reveal mechanisms behind miRNA turnoverPhD Thesis
MiR-test: A blood test for lung cancer early detectionJournal of the National Cancer Institute, vol. 107, (no. 6)
IsomiRage: From functional classification to differential expression of miRNA isoformsFrontiers in Bioengineering and Biotechnology, vol. 2, (no. SEP)
Differentiation-associated microRNAs antagonize the Rb-E2F pathway to restrict proliferationJournal of Cell Biology, vol. 199, (no. 1), pp. 77-95
A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early stage lung cancerEMBO Molecular Medicine, vol. 3, (no. 8), pp. 495-503
- Winner of a 2018 Roche individual grant "Roche per la ricerca" as Principal Investigator
- Winner of a 2016 Cariplo individual grant "Ricerca Biomedica condotta da Giovani Ricercatori 2016"as Principal Investigator.
- Winner of a 2014 AIRC/Fondazione Cariplo individual grant "TRIDEO" (Transforming IDeas in Oncological research award) as Principal Investigator
- 2012 Patent application, International Publication No WO/2012/089630 A1 PCT/EP2011/073868 A METHOD TO IDENTIFY ASYMPTOMATIC HIGH-RISK INDIVIDUALS WITH EARLY STAGE LUNG CANCER BY MEANS OF DETECTING miRNAs IN BIOLOGIC FLUIDS.
First Author: 6 Last Author: 1
Citations: 486 (Scopus)
Total Impact Factor: 102.4