Chromatin within the cell nucleus acquires a complex structure fundamental for genome function. The tridimensional organization of the genome abides tight rules that ensure proper genome usage and cell identity maintenance and has emerged as a hallmark of healthy cells.
We developed a new high-throughput sequencing technique, the Sequential Analysis of MacroMolecule accessibilitY (SAMMY-seq) to study different levels of chromatin solubility. We presented our improved versions of the protocol, to recover simultaneously euchromatin and heterochromatin. We applied SAMMY-seq on different cell populations highlighting a cell-specific organization of the chromatin. Moreover, tailored bioinformatic analysis allowed the A and B compartments determination, through the identification of discrete domains.
Primary prostate cancer (PCa) has a multifocal random growth and highly variable clinical course confusing the PCa diagnostic screenings. A reliable prognostic molecular signatures for the stratification of primary prostate cancers is still unavailable. We analyzed the epigenome of 17 chemo-naïve patients with putative PCa by SAMMY-seq on prostate biopsies. Transcriptome analysis (RNA-seq) was performed in parallel to confirm the functional effects of epigenome alterations. We identified two subgroups of cancer samples with different degrees of chromatin 3D architecture alterations, namely LDD (Low Degree of Decompartmentalization) and HDD (High Degree of Decompartmentalization). Gene expression analysis revealed a protective, antitumoral activity of the HDD subtype associated to changes in chromatin compartments and transcriptional repression. To discriminate HDD and LDD subtypes we derived a 21-genes transcriptional signature with prognostic relevance on prostate cancer patients confirmed across multiple cohorts. Our data highlight for the first time the impact of chromatin 3D conformation on early-stages primary prostate cancer. We propose a transcriptional signature derived from chromatin compartments driven stratification of patients as a novel prognostic tool to be adopted for prostate tumors at the time of diagnosis.
List of publication:
Frittoli E., Palamidessi A., Iannelli F., Zanardi F., Villa S., Barzaghi L., Abdo H., Cancila V., Beznuskenko G.V., della Chiara G., Pagani M., Malinverno C., Bhattacharya D., Pisati F., Yu W., Galimberti V., Bonizzi G., Martini E., Mironov A., Gioia U., Ascione F., Li Q., Havas K., Magni S., Lavagnino Z., Pennacchio F.A., Maiuri P., Caponi S., Mattarelli M., Martino S., d’Adda di Fagagna F., Rossi C., Lucioni M., Tancredi R., Pedrazzoli P., Vecchione A., Petrini C., Ferrari F., Lanzuolo C., Bertalot G., Nader G., Foiani M., Piel M., Cerbino R., Giavazzi F., Tripodo C. and Scita G. “Tissue fluidification promotes a cGAS/STING-mediated cytosolic DNA response in invasive breast cancer”,
Nature Materials 2022 Dec 29
Pegoli G., Milan M., Manti P.G., Bianchi A, Lucini F., Santarelli P., Bearzi C., Rizzi R. and Lanzuolo C
“Role of Cdkn2a in the Emery–Dreifuss Muscular Dystrophy Cardiac Phenotype”
Biomolecules 2021, Apr 6
Sebestyén E, Marullo F, Lucini F, Bianchi A, Petrini C, Valsoni S, Olivieri I, Antonelli L, Gregoretti F, Oliva G, Ferrari F and Lanzuolo C
“SAMMY-seq reveals early alteration of heterochromatin and deregulation of bivalent genes in Hutchinson-Gilford Progeria Syndrome”
Nat Commun 2020, Dec 8
Bianchi A, Mozzetta C, Pegoli G, Lucini F, Valsoni S, Rosti V, Petrini C, Cortesi A, Antonelli L, Gregoretti F, Oliva G, De Bardi M, Rizzi R, Bodega B, Pasini D, Ferrari F, Bearzi C and Lanzuolo C
“Dysfunctional polycomb transcriptional repression contributes to Lamin A/C dependent muscular dystrophy.”
J Clin Invest; 2020 Jan 30
Marullo F., Cesarini E., Antonelli L., Gregoretti F., Oliva G. and Lanzuolo C
” Nucleoplasmic Lamin A/C and Polycomb group of proteins: an evolutionarily conserved interplay “
Nucleus. 2016 Mar 1: 1-9
Cesarini E, Mozzetta C, Marullo F, Gregoretti F, Gargiulo A, Columbaro M., Cortesi A, Antonelli L, Di Pelino S, Squarzoni S, Palacios D, Zippo A, Bodega B, Oliva G and Lanzuolo C
“Lamin A/C sustains PcG proteins architecture maintaining transcriptional repression at target genes”
J Cell Biol. 2015 Nov 9;211(3):533-51