>> Research
Our Research
Our group aims to understand fundamental principles of gene regulation.
We are interested in understanding how alterations of epigenetic and chromatin regulatory systems contribute to the susceptibility and development of complex diseases.
We study mechanisms of gene expression at multiple levels, from the local action of epigenetic regulatory factors and long non-coding RNAs to the regulation of genome architecture. We use a combination of molecular biology, cell biology and biochemistry methods combined with epigenomic and transcriptomic high-throughput analyses to unravel the mechanisms underlying stem cell pluripotency, differentiation, reprogramming and cancer initiation/progression and to understand epigenetic regulatory processes in physiological and pathological conditions.
Current research themes and selected publications:
Genome organization in and around the nucleolus
The nucleolus is the most prominent substructure in the nucleus compartment, where transcription of hundreds of ribosomal RNA (rRNA) genes, rRNA processing, and ribosome subunit assembly takes place. The nucleolus is a membrane-less structure, which forms around regions of chromosomes containing stretches of rRNA gene repeats, known as nucleolar organizer regions (NORs). Transcription of rRNA genes is highly regulated through cell cycle and during cell differentiation and associated with accurate cell growth and proliferation. Furthermore, the chromatin state of rRNA genes together with the structure of the nucleolus is highly linked with the organization of the genome outside the nucleolus.
Our research aims to understand how chromatin and epigenetic mechanisms regulate rRNA genes and the role of the nucleolus in the regulation of genome organization and cell state.
Chromatin and epigenetic mechanisms in early development
Our research aims to elucidate how chromatin and epigenetic regulation is modulated during the early phase of development. We used different model systems to study how chromatin state and genome architecture are regulated during differentiation and the role of these processes in cell fate determination
Epigenetic mechanisms in cancer
We are interested in understanding how alterations of epigenetic and chromatin regulatory systems contribute to the susceptibility and development of complex diseases.
A major focus of the lab is the elucidation of epigenetic alterations in prostate cancer. The clinical behavior of a localized prostate cancer is highly variable with some men having indolent features that can be monitored without therapeutic intervention, or highly aggressive disease that requires intervention. The clinical heterogeneity of prostate cancer is underpinned by a heterogeneous molecular landscape, which posits one of the most confounding and complex factors underlying its diagnosis, prognosis, and treatment.
Our research aims to generate models of prostate cancer to define the contribution of epigenetic alterations in disease state that will serve for the discovery of prognostic markers of disease outcome, predictive biomarkers for drug response and targets for efficient therapy.
Genome organization in and around the nucleolus
Bersaglieri, C., Kresoja-Rakic, J., Gupta, S., Bär, D., Kuzyakiv, R., Santoro, R.
Genome-wide maps of nucleolus interactions reveal distinct layers of repressive chromatin domains
Gupta, S., Santoro, R.
Regulation and roles of the nucleolus in embryonic stem cells: from ribosome biogenesis to genome organization
Stem Cell Reports (2020) 15(6),1206-1219
Kresoja-Rakic J, Santoro R
Nucleolus and rRNA Gene Chromatin in Early Embryo Development
Trends Genet. 2019 Jul pii: S0168-9525(19)30125-8
Bersaglieri C, Santoro R.
Genome Organization in and around the Nucleolus
Cells 2019 Jun 12;8(6). pii: E579
Leone S, Bär D, Slabber CF, Dalcher D, Santoro R
The RNA helicase DHX9 establishes nucleolar heterochromatin and this activity is required for embryonic stem cell differentiation
EMBO Reports 2017 Jun; 18:1248-1262
Savić N, Bär D, Leone S, Frommel SC, Weber FA, Vollenweider E, Ferrari E, Ziegler U, Kaech A, Shakhova O, Cinelli P, Santoro R
lncrna maturation to initiate heterochromatin formation in the nucleolus is required for exit from pluripotency in ESCs
Cell Stem Cell. 2014 Dec 4;15(6):720-34
Guetg, C., Scheifele, F., Rosenthal, F., Hottiger, M.O. and Santoro, R.
Inheritance of silent rDNA chromatin is mediated by PARP1 via non-coding RNA.
Molecular Cell 45, 790-800, 2012
Guetg C., Lienemann P., Sirri V., Grummt I., Hernandez-Verdu D., Hottiger M.O., Fussenegger M. and Santoro R.:
The NoRC complex mediates heterochromatin and stability of silent rRNA genes and centromeric repeats
EMBO J. 29(13): 2135-2146, 2010
Chromatin and epigenetic mechanisms in early development
Dalcher, D., Tan, JY, Bersaglieri, C., Peña-Hernández, R., Vollenweider, E., Zeyen, S., Schmid, MW., Bianchi, V., Butz, S., Roganowicz, M., Kuzyakiv, R., Baubec, T., Marques, AC., Santoro, R.
BAZ2A safeguards genome architecture of ground-state pluripotent stem cells
EMBO J (2020) 39:e105606
Kresoja-Rakic J, Santoro R
Nucleolus and rRNA Gene Chromatin in Early Embryo Development
Trends Genet. 2019 Jul pii: S0168-9525(19)30125-8
Wyck S, Herrera C, Requena CE, Bittner L, Hajkova P, Bollwein H, Santoro R
Oxidative stress in sperm affects the epigenetic reprogramming in early embryonic development
Epigenetics & Chromatin 2018 Oct 17;11(1):60
Graf U, Casanova E, Wyck S, Dalcher D, Gatti M, Vollenweider E, Okoniewski M, Weber FA, Patel SS, Schmid M, Li J, Sharif J, Wanner GA, Koseki H, Wong J, Pelczar P, Penengo L, Santoro R*, Cinelli P*.
*Senior and corresponding authors
Pramel7 mediates ground state pluripotency through proteasomal-epigenetic combined pathways
Nature Cell Biology 2017 Jul;19(7):763-773
Chromatin and epigenetic mechanisms in cancer
Peña-Hernández, R., Aprigliano, R., Frommel, S., Pietrzak, K., Steiger, S., Roganowicz, M., Lerra, L., Bizzarro, J., Santoro, R.
BAZ2A-mediated repression via H3K14ac-marked enhancers promotes prostate cancer stem cells
EMBO Rep (2021) e53014
Diener,J., Baggiolini, A., Pernebrink, M., Dalcher, D., Lerra, L., Cheng, P.F., Varum, S., Häusel, J., Stierli, S., Treier, M., Studer, L., Basler, K., Levesque, M.P., Dummer, R., Santoro, R., Cantù, C., Sommer, L.
Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4
Nat Commun (2021) 12(1):5056.
Pietrzak, K., Kuzyakiv, R., Simon, R., Bolis, M., Bär, D., Aprigliano, R., Theurillat, JP., Sauter, G., Santoror, R.
TIP5 primes prostate luminal cells for the oncogenic transformation mediated by PTEN-loss
Proc Natl Acad Sci USA (2020) 117, 3637-3647
Zingg D, Debbache J, Peña-Hernández R, Antunes AT, Schaefer SM, Cheng PF, Zimmerli D, Haeusel J, Calçada RR, Tuncer E, Zhang Y, Bossart R, Wong KK, Basler K, Dummer R, Santoro R, Levesque MP, Sommer L
EZH2-Mediated Primary Cilium Deconstruction Drives Metastatic Melanoma Formation
Cancer Cell. 2018 Jul 9;34(1):69-84 e 14.
Gu L, Frommel SC, Oakes CC, Simon R, Grupp K, Gerig CY, Bär D, Robinson MD, Baer C, Weiss M, Gu Z, Schapira M, Kuner R, Sültmann H, Provenzano M; ICGC Project on Early Onset Prostate Cancer, Yaspo ML, Brors B, Korbel J, Schlomm T, Sauter G, Eils R, Plass C, Santoro R
BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence
Nature Genetics 2015 Jan;47(1):22-30
Zingg D, Debbache J, Schaefer SM, Tuncer E, Frommel SC, Cheng P, Arenas-Ramirez N, Haeusel J, Zhang Y, Bonalli M, McCabe MT, Creasy CL, Levesque MP, Boyman O, Santoro R, Shakhova O, Dummer R, Sommer L
The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors
Nature Communications 2015 Jan 22;6:6051