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Paolo Sassone-Corsi
Born	June 8, 1956 Naples, Italy
Education	Ph.D., University of Naples, Italy, 1979
Website	https://www.faculty.uci.edu/profile.cfm?faculty_id=5402

Paolo Sassone-Corsi (born 8 June 1956) ^[1]is an Italian neuroscientist and molecular geneticist. He is currently a faculty member of the University of California Irvine, where he serves as the Director for the Center for Epigenetics and Metabolism. Sassone-Corsi's studies have added to the scientific understanding of the negative feedback loop controlling mammalian circadian rhythms by discovering the molecular links with metabolism and epigenetics. Sassone-Corsi’s work focuses on chromatin remodeling, signal transduction mechanisms which influence nuclear functions, and the role of circadian clocks in metabolism and diseases^[3].

Early Life and Academic Career

Paolo Sassone-Corsi was born in Naples (Italy), the last of three brothers. His father was an accountant and his mother a literature teacher. During classical studies he developed a scientific interest in astronomy, which he still cultivates. In 1979, he obtained his Ph.D. in Biological Science from the University of Naples with a specialization in molecular genetics. After his Ph.D. he was a post-doctoral fellow in Strasbourg (France) and at The Salk Institute (San Diego, USA). He worked for several years at the Institut de Génétique et de Biologie Moléculaire et Cellulaire in Strasbourg (France) and still holds the position of Directeur de Recherche in the French National Center for Scientific Research (CNRS). Sassone-Corsi is currently a Donald Bren Professor in Biological Chemistry at the University of California, Irvine School of Medicine. He is also the Director of the Center for Epigenetics and Metabolism. Sassone-Corsi holds a Joint Appointment in the Department of Microbiology and Molecular Genetics at UCI School of Medicine and in the Department of Pharmaceutical Sciences at UCI College of Health Sciences. Sassone-Corsi was formerly the Chair of the Department of Pharmacology at UCI from 2006-2011. He is also an External Professor of the Max-Planck Institute (Germany). He also  holds memberships in several professional societies including European Molecular Biology Organization, the Society for Research on Biological Rhythms (USA) and the Endocrine Society (USA).

Research Interests and Achievements

Linking Signal Transduction to Gene Regulation

While in Strasbourg in the early 80s, Sassone-Corsi studied gene expression and initially contributed to the characterization of the TATA-box and enhancer plus promoter elements. Moving to the Salk Institute, his interests fell largely in cellular biology, and he studied how various signaling pathways control gene expression by modifying transcription factors. Sassone-Corsi’s early work focused on the induction of the proto-oncogene, fos; he discovered its autoregulatory feedback loop. During these studies he discovered that the oncoproteins FOS and JUN dimerize to generate the transcription factor AP-1 and that they do so through the leucine-zipper domain. While building his own research group, he became specifically interested in the signal transduction of cyclic 3‘,5’-adenosine monophosphate(cAMP) and discovered the cAMP Response Element Modulator (CREM). CREM functions as a modulator of cells' cAMP-responses by dimerizing with the transcription factor CREB in a variety of endocrine and neuronal settings. Specifically, CREM expression in the pineal gland is highly rhythmic and contributes to the circadian oscillation of the hormone melatonin.

Sassone-Corsi determined that phosphorylation targets multiple transcription factors in the nucleus. These transcription factors specifically comprise a family of activators or repressors that can dimerize and bind to cAMP Response Elements (CREs) in the genome, ultimately leading to the modulation of a large number of cAMP-responsive genes.

Control of Germ Cells

Sassone-Corsi discovered that cAMP Response Element Modulator (CREM) is a critical regulator of spermatogenesis as it drives the transcriptional program that leads to the formation of mature germ cells. This regulation is governed by the hypothalamic-pituitary axis through FSH-dependent signaling and the alternative usage of poly-adenylation sites in the CREM gene. CREM gene-null mice display a complete block of spermatogenesis and increased germ cells apoptosis. CREM function as a transcriptional activator in germ cells, and it is coupled by the co-activator ACT and the germ-cell specific kinesin KIF17b. Sassone-Corsi also revealed the composition and function of the chromatoid body, a perinuclear structure that operates as a germ cell-specific RNA processing center. Both microRNA and RNA-decay pathways converge to the chromatoid body where PIWI/Argonaute and Dicer-associated proteins accumulate.

Early Interest in Mammalian Clocks and Discovery of Peripheral Oscillators

Sassone-Corsi’s research in mammalian clocks began with studies on the transcriptional regulation of melatonin synthesis via a cAMP Response Element Modulator (CREM) feedback loop. Circadian and light-responsive expression of CREM in the pineal gland results in cyclic control of the serotonin N-acetyltransferase, an enzyme that catalyzes the rate-limiting step in the biosynthesis of the circadian hormone melatonin . He later started examining the negative feedback loop of mammalian clock genes.

Interested in light-transduction in the clock, Sassone-Corsi utilized zebrafish as a vertebrate model and revealed that peripheral organs as well as zebrafish cultured cells are light responsive and are intrinsically able to sustain circadian oscillations. He also focused on the cryptochrome family of photoreceptors and identified these proteins as essential for phototransduction in zebrafish.

Epigenetic Control of the Mammalian Clock

Sassone-Corsi largely studies the epigenetic modification of the circadian feedback loop conserved among many organisms. In this loop, there are positive and negative regulators: in the mammalian clock machinery, the negative regulators are the crytochrome (CRY1 and CRY2) and period (PER1, PER2, PER3) families. The positive regulators are CLOCK and BMAL1. The CLOCK and BMAL1 transcription factors use their PAS domains to heterodimerize. The heterodimer binds to the E-boxes, which are promoter elements, of clock-controlled genes (CCGs) to induce their expression. More specifically, CLOCK and BMAL1 are transcription factors for CRY and PER. Sassone-Corsi helped to characterize how epigenetic mechanisms like histone modification produce plasticity within the negative feedback loop. Additionally, he has helped to determine that such epigenetic mechanisms often follow circadian rhythms.

Sassone-Corsi generated the first study which characterized chromatin remodeling in suprachiasmatic nucleus (SCN) neurons in response to light. Multiple scientists have subsequently shown that light exposure results in rapid phosphorylation of histone 3 on serine 10 (H3-S10) in the SCN. This rapid phosphorylation induces the expression of immediate-early genes like Fos and circadian genes like Per1. This finding proved that chromatin remodeling plays a central role in circadian gene expression.

Sassone-Corsi has also contributed to the properties of one of the major circadian transcription factors, CLOCK. He helped determine that CLOCK has intrinsic histone acetyltransferase (HAT) activity. Given that it binds E-boxes of CCGs, CLOCK is thought to participate in modifying chromatin at the promoters of circadian clock genes; CLOCK specifically targets histone 3 lysine 9 and 14 (H3K9/K14). Increased H3K9/K14 acetylation enhances CCG expression. Additionally, CLOCK's HAT activity also directly acetylates non-histone components like its binding partner, BMAL1. Sassone-Corsi helped show that acetylation of BMAL1 occurs on a conserved region that facilitates the CRY-dependent repression of CLOCK, BMAL1, and subsequently the CCGs. CLOCK has been found to acetylate the glucocorticoid receptor (GR) and metabolic enzymes, such as Ass1 (arginosuccinate synthetase); in doing so, CLOCK helps control ureagenesis.

Linking Metabolism to Epigenetics by the Circadian Clock

Scientists began searching for a histone deacetylase which would participate in the transcriptional down-regulation of clock-controlled genes (CCGs). Sassone-Corsi led one of two independent groups that determined that SIRT1 is a histone deacetylase (HDAC) that counters CLOCK. SIRT1 is part of the sirtuin family which is a class III HDAC. As a class III HDAC, SIRT1 HDAC activity depends on NAD+, a coenzyme that is directly linked to metabolism and aging. Sassone-Corsi’s group determined that SIRT1 protein levels are not circadian, but SIRT1 activity is. They found that the CLOCK-BMAL1 heterodimer interacts with SIRT1 and recruits it to the promoters of CCGs. They then hypothesized that SIRT1 affects clock gene expression by modulating CLOCK-mediated acetylation of histone 10 lysine 9 and 14 (H3K9/K14) and deacetylating BMAL1 and PER2. Furthermore, they found that BMAL1 acetylation was compromised in liver-specific SIRT1 mutant mice. This finding led them to conclude that circadian SIRT1 activity is especially important for transcription cycles in metabolic tissues.

Sassone-Corsi then lead one of two independent groups that determined the circadian control by CLOCK-BMAL1 of the Nicotinamide Phosphoribosyltransferase (Nampt) gene that encodes NAMPT, the rate-limiting enzyme in the NAD+ salvage pathway. NAMPT contributes to the conversion of nicotinamide, generated by NAD-consuming enzymes, to nicotinamide mononucleotide which enables NAD+ biosynthesis in mammals. This regulatory pathway leads to circadian oscillations of NAD+ intracellular levels and the consequent cyclic activation of SIRT1. Thus, the clock system links NAD+ metabolism to epigenetic regulation.

CLOCK associates with a mixed lineage leukemia 1 (MLL1), a methyltransferase. Sassone-Corsi has shown that MLL1 contributes to CLOCK-BMAL1 binding to target promoters on chromatin. MLL1 then methylates H3 at lysine 4 sites (H3K4) – methylation at these sites enhances H3K9/K14 acetylation, thereby leading to greater gene expression. In eukaryotes, H3K4 trimethylation is widely accepted as a unique epigenetic mark that denotes active chromatin states, further confirming that MLL1 activity ultimately enhances circadian clock gene expression.

Reprogramming the Circadian Clock

More recently, Sassone-Corsi has been studying how circadian rhythms relate to cellular metabolism. His work has identified a multi-tissue metabolism network that follows a circadian rhythm, and he noted that overall, it seems like metabolic functions that follow circadian rhythms affect most levels of organization; in other words, the metabolism of both individual cells and organ systems exhibit circadian rhythms. Sassone-Corsi investigated the effect of misalignment in these networks and the increased propensity of disease associated with misalignment. External factors that affected metabolic functions, such as high-fat diets, were shown to reprogram metabolic rhythms in mice. Reprogramming is achieved by the circadian activation of alternative transcriptional and metabolic pathways. This was also observed during aging and the beneficial effect of caloric restriction. Sassone-Corsi has shown that the liver circadian clock is intimately connected to the process of aging.

Additional studies have examined how other nutritional regimes, including the ketogenic diet and fasting, influence the circadian clock. In the fasting experiments, mice were put in three treatment conditions: Fed (allowed to eat freely), Fast (24 hours fasting before tissue collection) and Refeed (underwent 24-hr fasting, followed by a 24-hr with feeding). Results showed that fasting can affect circadian rhythms and rewire metabolism: researchers found a reduction in oxygen consumption, respiratory exchange ratio, and energy expenditure post-fasting. Gene regulation in different tissues had variable responses to the fasting. Refeeding conditions showed evidence of the reversibility of some effects of fasting. Ultimately, Sassone-Corsi suggested that optimal fasting could positively affect cellular function. The implication of Sassone-Corsi’s research and hypothesis on metabolic function is that manipulations of one’s diet can protect against age-associated diseases; Sassone-Corsi suggested that optimizing one’s nutrition plan can greatly benefit people’s health.

Communicating Clocks and Oncogenesis

Sassone-Corsi also suggested a link between circadian clocks and cancer. He noted that many circadian genes are closely linked to metabolism and cellular proliferation: SIRT1 plays an important role in regulating metabolism. Additionally, Cell cycle regulator genes including WEE1, MYC and cyclin D1 are affected by the circadian clock. Given these connections, changes in the circadian clock can affect the cell cycle as well as metabolism in a negative way; altering circadian cycles can potentially result in aberrant cell proliferation. Since uncontrolled cell proliferation is associated with cancer, it is possible that circadian cycle disruptions may play a role in oncogenesis. Sassone-Corsi suggested that a greater understanding of the molecular links between the circadian clock and the cell cycle could inform human neoplasia therapy.

By studying mice with lung adenocarcinoma Sassone-Corsi revealed the rewiring of circadian liver metabolism at distance. This finding indicated that clocks communicate metabolically. By generating an Atlas of circadian metabolism through high-throughput metabolomics of several mouse tissues, both coordination and communication of clocks has been illustrated.

Notable Publications

Circadian regulator CLOCK is a histone acetyltransferase. Doi M, Hirayama J, Sassone-Corsi P. Cell. 2006 May 5;125(3): 497-508. doi: 10.1016/j.cell.2006.03.033. PMID: 16678094

CLOCK-mediated acetylation of BMAL1 controls circadian function. Hirayama J, Sahar S, Grimaldi B, Tamaru T, Takamatsu K, Nakahata Y, Sassone-Corsi P. Nature. 2007 Dec 13;450(7172). doi: 10.1038/nature06394. PMID: 18075593

The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Nakahata, Y., Kaluzova, M., Grimaldi, B., Sahar, S., Hirayama, J., Chen, D., Guarente, L.P., and Sassone-Corsi, P. Cell. 2008 July 25;134(2): 329-340. doi: 10.1016/j.cell.2008.07.002. PMID: 18662547

The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP, Sassone-Corsi P. Cell. 2008 Jul 25;134(2):329-40. doi: 10.1016/j.cell.2008.07.002. PMID: 18662547

Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P. Science. 2009 May 1;324(5927):654-7. doi: 10.1126/science.1170803. Epub 2009 Mar 12. PMID: 19286518

The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. Katada, S., and Sassone-Corsi, P. Nature Structural and Molecular Biology, 2010 November 28;17(12): 1414-1421. doi: 10.1038/nsmb.1961. PMID: 21113167

De Luca, E, and Sassone-Corsi, P. Ti sembra il caso?: Schermaglia fra un narratore e un biologo. Milan: Feltrinelli Editore. 2013.

Reprogramming of the circadian clock by nutritional challenge. Eckel-Mahan KL, Patel VR, de Mateo S, Orozco-Solis R, Ceglia NJ, Sahar S, Dilag-Penilla SA, Dyar KA, Baldi P, Sassone-Corsi P. Cell. 2013 Dec 19;155(7):1464-78. doi: 10.1016/j.cell.2013.11.034. PMID: 24360271

Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis. Masri S, Papagiannakopoulos T, Kinouchi K, Liu Y, Cervantes M, Baldi P, Jacks T, Sassone-Corsi P. Cell. 2016 May 5;165(4):896-909. doi: 10.1016/j.cell.2016.04.039. PMID: 27153497

Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging. Sato S, Solanas G, Peixoto FO, Bee L, Symeonidi A, Schmidt MS, Brenner C, Masri S, Benitah SA, Sassone-Corsi P. Cell. 2017 Aug 10;170(4):664-677.e11. doi: 10.1016/j.cell.2017.07.042. PMID: 28802039

Distinct Circadian Signatures in Liver and Gut Clocks Revealed by Ketogenic Diet. Tognini P, Murakami M, Liu Y, Eckel-Mahan KL, Newman JC, Verdin E, Baldi P, Sassone-Corsi P. Cell Metab. 2017 Sep 5;26(3):523-538.e5. doi: 10.1016/j.cmet.2017.08.015. PMID: 28877456

Atlas of Circadian Metabolism Reveals System-wide Coordination and Communication between Clocks. Dyar KA, Lutter D, Artati A, Ceglia NJ, Liu Y, Armenta D, Jastroch M, Schneider S, de Mateo S, Cervantes M, Abbondante S, Tognini P, Orozco-Solis R, Kinouchi K, Wang C, Swerdloff R, Nadeef S, Masri S, Magistretti P, Orlando V, Borrelli E, Uhlenhaut NH, Baldi P, Adamski J, Tschöp MH, Eckel-Mahan K, Sassone-Corsi P. Cell. 2018 Sep 6;174(6):1571-1585.e11. doi: 10.1016/j.cell.2018.08.042. PMID: 30193114

The Emerging Link Between Cancer, Metabolism, and Circadian Rhythms. Masri-Corsi S, Sassone-Corsi P. Nature Medicine. 2018 December 06;24:1795-1803. doi: 10.1038/s41591-018-0271-8 PMID: 30523327

Fasting Imparts a Switch to Alternative Daily Pathways in Liver and Muscle. Kinouchi K, Magnan C, Ceglia N, Liu Y, Cervantes M, Pastore N, Huynh T, Ballabio A, Baldi P, Masri S, Sassone-Corsi P. Cell Rep. 2018 Dec 18;25(12):3299-3314.e6. doi: 10.1016/j.celrep.2018.11.077. PMID: 30566858

Honors and Awards

Philips European Award for Young Investigators (1977)

Member of the European Molecular Biology Organization (1990)

EMBO Gold Medal (1994)

Rosen Prize (Fondation de la Recherche Médicale), France (1996)

Grand Prix Liliane Bettencourt pour la Recherche, France (1997)

Segerfalk Award Lecture, Lund University, Sweden (2001)

Grand Prix Charles-Léopold Mayer de l’Académie des Sciences, France (2003)

ISI Highly Cited (2003)

Edwin B. Astwood Award Lecture of The Endocrine Society, USA (2004)

The Umesono Memorial Award Lecture, The Salk Institute, San Diego (2004)

CNRS Silver Medal, France (2004)

Distinguished Professor Medal, University of California, Irvine, USA (2006)

Athalie Clarke Achievement Award, University of California, Irvine, School of Medicine (2010)

Roy O. Greep Award Lecture, 2011 Laureate Award by The Endocrine Society, USA (2011)

The Ipsen Award in Endocrinology (2011)

External Professor, Max Planck Society, Germany (2011)

Transatlantic Medal of The Society for Endocrinology, UK (2012)

Dr. Henry Friesen Plenary Lecture Award, Canada (2013)

Fellow, American Association for the Advancement of Science, USA (2014)

August and Marie Krogh Medal, Denmark (2015)

Leonardo da Vinci Gold Medal, FMSI Federation, Italy (2016)

Albert Hogan Memorial Award, University of Missouri (2017)

University of California Distinguished Faculty Award for Research (2018)