Sebastian Gregoricchio
Verified @gmail.com
Scopus Publications
- Regulatory grammar in human promoters uncovered by MPRA-based deep learning
Lucía Barbadilla-Martínez, Noud Klaassen, Vinícius H. Franceschini-Santos, Jérémie Breda, Hatice Yücel, Miguel Hernández-Quiles, Tijs van Lieshout, Carlos G. Urzua Traslaviña, Minh Chau Luong Boi, Maryam Akbarzadeh, Celia Hermana-Garcia-Agullo, Sebastian Gregoricchio, Marcel de Haas, Roy Straver, Sarah Derks, Wilbert Zwart, Emile Voest, Lude Franke, Michiel Vermeulen, Jeroen de Ridder, Bas van Steensel
Nature, 2026
Promoters are the core regulatory elements of all genes. Their activity ensures the correct transcription level of each individual gene, which is essential for cellular homeostasis and responses to a wide range of signals. One of the major challenges in genomics is to build computational models that accurately predict genome-wide gene expression from the sequences of regulatory elements1. Here we present promoter activity regulatory model (PARM), a cell-type-specific deep-learning model trained on specially designed massively parallel reporter assays (MPRAs) that query human promoter sequences. PARM is experimentally and computationally lightweight so that cell-type-specific and condition-specific models can be generated that reliably predict autonomous promoter activity across the genome from the DNA sequence alone. PARM can also design purely synthetic strong promoters. We leveraged PARM to systematically identify binding sites of transcription factors that probably contribute to the activity of each natural human promoter and to detect the rewiring of these regulatory interactions after various stimuli to the cells. We also uncovered and experimentally confirmed substantial positional preferences of transcription factors that differ between activating and repressive regulatory functions and a complex grammar of motif–motif interactions. Our approach provides a highly economic strategy towards a deeper understanding of the dynamic regulation of human promoters by transcription factors. PARM is a deep-learning model trained on data from massively parallel reporter assays to help predict promoter activity in different human cell types, design synthetic promoters and identify key features of regulatory promoter grammar. - DEprot: a comprehensive R-package for the analysis of label-free quantitation mass spectrometry data
Nils Eickhoff, Liesbeth Hoekman, Onno Bleijerveld, Andries M Bergman, Wilbert Zwart, Sebastian Gregoricchio
Nar Genomics and Bioinformatics, 2026
In recent years, studies investigating protein–protein interactions on a proteome-wide scale have increased exponentially. These developments were achieved through implementation of new techniques, as well as improvements in mass spectrometry hardware. However, issues specific to this type of technique, such as distinct imputation of random and not-at-random missing proteins, have not been completely addressed. Here, we present DEprot, an R-package providing a comprehensive toolset for end-to-end analysis and visualization of proteomics data. Moreover, we implemented a serial imputation strategy for handling non-random missing values, particularly suitable for protein enrichment techniques and knockout conditions. - Fasting boosts breast cancer therapy efficacy via glucocorticoid activation
Nuno Padrão, Tesa M. Severson, Sebastian Gregoricchio, Ana Guijarro, Catrin Lutz, Daniel Taranto, Stefan Hutten, Francesca Ligorio, Angelica Persia, Merel Roest, Joyce Sanders, Ji-Ying Song, Sara Pires-Oliveira, Maria Donaldson Collier, Hugo Horlings, Livia Pisciotta, Filippo de Braud, Claudio Vernieri, Leila Akkari, Jos Jonkers, Alessio Nencioni, Irene Caffa, Wilbert Zwart
Nature, 2026
The majority of breast cancers are driven by oestrogen receptor-α (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients1. However, resistance is common and tumours often progress after years of endocrine suppression2. Periodic fasting enhances the efficacy of standard endocrine therapy and delays acquired drug resistance, although the underlying mechanisms remain unclear3. Here we show that fasting induces extensive epigenetic reprogramming in ERα-positive breast cancer xenografts when combined with endocrine therapy, with large-scale activation of glucocorticoid receptor (GR) and progesterone receptor signalling and concomitant reduction in the activity of activator protein-1 (AP-1) family members. GR-driven gene programmes are selectively activated in in vivo models of ERα-positive breast cancer during fasting, and GR knockout hinders the anti-tumour effects of fasting combined with tamoxifen. Exogenous administration of GR ligands recapitulates fasting-enhanced anti-oestrogen action, thus promoting tumour regression. Patients undergoing a cyclic fasting-mimicking diet exhibited increased blood progesterone and cortisol concentrations. Additionally, tumours collected after the fasting-mimicking diet showed an inverse correlation of GR activation with proliferation markers, providing clinical confirmation of our observations in animal models. Our results indicate that GR activation has a pivotal role in the ability of fasting to enhance endocrine therapy activity in breast cancer and suggest that corticosteroid administration should be evaluated as an adjuvant to endocrine therapy in this setting. Beneficial effects of fasting combined with endocrine therapy for oestrogen receptor-α-expressing breast cancers can be recapitulated using exogenous glucocorticoid receptor ligands instead of fasting to reduce harmful effects. - TRIM33 loss reduces androgen receptor transcriptional output and H2BK120 ubiquitination
Nils Eickhoff, Janina Janetzko, Nuno Padrão, Sebastian Gregoricchio, Joseph C. Siefert, Liesbeth Hoekman, Simon Linder, Onno Bleijerveld, Andries M. Bergman, Wilbert Zwart
Communications Biology, 2025
The Androgen Receptor (AR) is a ligand-dependent transcription factor that drives prostate cancer development and progression. Although, a detailed effect on AR biology has been described for a number of interacting proteins, many AR coregulators remain to be characterized in relation to their distinct impact on AR function. Here, we describe TRIM33 as a conserved AR-interactor across multiple prostate cancer cell lines. We observed that TRIM33 and AR share overall chromatin interaction profiles, in which TRIM33 is involved in downstream responsive transcriptomic output. In contrast to prior reports, we show that TRIM33 does not impact AR protein stability, but instead propose a model in which TRIM33 facilitates maximal AR activity by interfering with H2BK120 ubiquitination levels. The authors study the role of TRIM33 in androgen receptor (AR) transcriptional activity. They show that TRIM33 and AR co-occupy most of their genomic binding sites and TRIM33 loss altered expression of a subset of AR-responsive genes. - Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations
Sebastian Gregoricchio, Aleksandar Kojic, Marlous Hoogstraat, Karianne Schuurman, Suzan Stelloo, Tesa M. Severson, Tracy A. O’Mara, Marjolein Droog, Abhishek A. Singh, Dylan M. Glubb, Lodewyk F. A. Wessels, Michiel Vermeulen, Flora E. van Leeuwen, Wilbert Zwart
Genome Biology, 2025
BACKGROUND: The incidence and mortality of endometrial cancer (EC) is on the rise. Eighty-five percent of ECs depend on estrogen receptor alpha (ERα) for proliferation, but little is known about its transcriptional regulation in these tumors. RESULTS: We generate epigenomics, transcriptomics, and Hi-C datastreams in healthy and tumor endometrial tissues, identifying robust ERα reprogramming and profound alterations in 3D genome organization that lead to a gain of tumor-specific enhancer activity during EC development. Integration with endometrial cancer risk single-nucleotide polymorphisms and whole-genome sequencing data from primary tumors and metastatic samples reveals a striking enrichment of risk variants and non-coding somatic mutations at tumor-enriched ERα sites. Through machine learning-based predictions and interaction proteomics analyses, we identify an enhancer mutation which alters 3D genome conformation, impairing recruitment of the transcriptional repressor EHMT2/G9a/KMT1C, thereby alleviating transcriptional repression of ESR1 in EC. CONCLUSIONS: In summary, we identify a complex genomic-epigenomic interplay in EC development and progression, altering 3D genome organization to enhance expression of the critical driver ERα. - Germline–Somatic Liaison Dictates Cancer Subtypes via de novo Steroid Biosynthesis
Paola Gasperini, Alessandro Alaimo, Blerta Stringa, Yoon-Mi Chung, Yari Ciani, Francesca Lorenzin, Giulia Fracassi, Yanis Zekri, Francesco Orlando, Orsetta Quaini, Sebastian Gregoricchio, Gianluca Petris, Antonio Casini, Christopher E. Barbieri, Wilbert Zwart, Anna Cereseto, Nima Sharifi, Andrea Lunardi, Francesca Demichelis
Cancer Discovery, 2025
The biological mechanisms underlying the cooperation between germline genetic variants and somatic mutations during carcinogenesis are rarely elucidated. In this study, characterizing isogenic prostate cancer cell lines, we dissected the interplay between a germline variant at the 7p14.3 locus (rs1376350, G>A) and early recurrent prostate cancer–specific mutation in the speckle-type POZ protein (SPOP) gene across human prostate adenocarcinomas. The transcriptomes of multiple edited models pointed to GLI3 and the Hedgehog signaling pathway in a genotype-specific manner, whereas SPOP mutation and androgen receptor stimulation promote GLI3 accumulation in the full-length, transcriptionally active form. This, in turn, triggers the cell-autonomous production of steroids that prostate cancer relies on, in line with the enhanced responsiveness of SPOP-mutated prostate cancer to androgen deprivation therapy. These data demonstrate that germline variants dictate prostate cancer somatic evolution and suggest opportunities to jointly model germline–somatic relationship to help untangle the complexity of human cancer. Significance: Significant heritability is observed for common cancer types worldwide. The molecular mechanisms by which inherited genetics facilitate cancer initiation might transit through its cooperation with specific somatic events that then dictate the tumor features. Through a germline–somatic tandem leading to steroid biosynthesis, we suggest a paradigm to study cancer initiation. - A 3D genome compendium of breast cancer progression
Teun van den Brand, Maria Donaldson Collier, Koen D. Flach, Sebastian Gregoricchio, Isabel Mayayo-Peralta, Zhanna Dauyey, Karianne Schuurman, Hans Teunissen, Wilbert Zwart, Elzo de Wit
Iscience, 2025
During cancer development and progression massive alterations in gene expression are observed. Gene regulation occurs within the context of the 3D genome. However, the impact of disease progression on 3D genome organization remains poorly understood. Using breast cancer as a model, we have profiled the 3D genome throughout the natural course of the disease; from development to progression. Uniquely, we analyzed tumors from the same patients, enabling us to gauge the extent of changes that happen upon metastasis. Our results show that the organization of the genome at the level of topologically associating domains (TADs) and compartments upon tumorigenesis and metastasis, is remarkably stable. However, in pleural metastases, representing heavily pretreated progressive disease, the 3D genome is massively affected, and highly heterogeneous between patients, both on the compartment and TAD level. Our data reveal that disease progression in breast cancer is associated with a progressive unraveling of the 3D genome. - Tamoxifen induces PI3K activation in uterine cancer
Kirsten Kübler, Agostina Nardone, Shankara Anand, Daniel Gurevich, Jianjiong Gao, Marjolein Droog, Francisco Hermida-Prado, Tara Akhshi, Ariel Feiglin, Avery S. Feit, Gabriella Cohen Feit, Gwen Dackus, Matthew Pun, Yanan Kuang, Justin Cha, Mendy Miller, Sebastian Gregoricchio, Mirthe Lanfermeijer, Sten Cornelissen, William J. Gibson, Cloud P. Paweletz, Eliezer M. Van Allen, Flora E. van Leeuwen, Petra M. Nederlof, Quang-Dé Nguyen, Marian J. E. Mourits, Milan Radovich, Ignaty Leshchiner, Chip Stewart, Ursula A. Matulonis, Wilbert Zwart, Yosef E. Maruvka, Gad Getz, Rinath Jeselsohn
Nature Genetics, 2025
Mutagenic processes and clonal selection contribute to the development of therapy-associated secondary neoplasms, a known complication of cancer treatment. The association between tamoxifen therapy and secondary uterine cancers is uncommon but well established; however, the genetic mechanisms underlying tamoxifen-driven tumorigenesis remain unclear. We find that oncogenic PIK3CA mutations, common in spontaneously arising estrogen-associated de novo uterine cancer, are significantly less frequent in tamoxifen-associated tumors. In vivo, tamoxifen-induced estrogen receptor stimulation activates phosphoinositide 3-kinase (PI3K) signaling in normal mouse uterine tissue, potentially eliminating the selective benefit of PI3K-activating mutations in tamoxifen-associated uterine cancer. Together, we present a unique pathway of therapy-associated carcinogenesis in which tamoxifen-induced activation of the PI3K pathway acts as a non-genetic driver event, contributing to the multistep model of uterine carcinogenesis. While this PI3K mechanism is specific to tamoxifen-associated uterine cancer, the concept of treatment-induced signaling events may have broader applicability to other routes of tumorigenesis. - TRIM24 as a therapeutic target in endocrine treatment–resistant breast cancer
Nuno Padrão, Sebastian Gregoricchio, Nils Eickhoff, Jing Dong, Lara Luzietti, Daniela Bossi, Tesa M. Severson, Joseph Siefert, Arianna Calcinotto, Laki Buluwela, Maria Donaldson Collier, Simak Ali, Leonie Young, Jean-Philippe Theurillat, Damir Varešlija, Wilbert Zwart
Proceedings of the National Academy of Sciences of the United States of America, 2025
While Estrogen receptor alpha (ERα)+ breast cancer treatment is considered effective, resistance to endocrine therapy is common. Since ERα is still the main driver in most therapy-resistant tumors, alternative therapeutic strategies are needed to disrupt ERα transcriptional activity. In this work, we position TRIM24 as a therapeutic target in endocrine resistance, given its role as a key component of the ERα transcriptional complex. TRIM24 interacts with ERα and other well-known ERα cofactors to facilitate ERα chromatin interactions and allows for maintenance of active histone marks including H3K23ac and H3K27ac. Consequently, genetic perturbation of TRIM24 abrogates ERα-driven transcriptional programs and reduces tumor cell proliferation capacity. Using a recently developed degrader targeting TRIM24, ERα-driven transcriptional output and growth were blocked, effectively treating not only endocrine-responsive cell lines but also drug-resistant derivatives thereof as well as cell line models bearing activating ESR1 point mutations. Finally, using human tumor-derived organoid models, we could show the efficacy of TRIM24 degrader in the endocrine-responsive and -resistant setting. Overall, our study positions TRIM24 as a central component for the integrity and activity of the ERα transcriptional complex, with degradation-mediated perturbation of TRIM24 as a promising therapeutic avenue in the treatment of primary and endocrine resistance breast cancer. - Epigenetic profiling identifies markers of endocrine resistance and therapeutic options for metastatic castration-resistant prostate cancer
Tesa M. Severson, Emma Minnee, Yanyun Zhu, Karianne Schuurman, Holly M. Nguyen, Lisha G. Brown, Sini Hakkola, Renee Menezes, Sebastian Gregoricchio, Yongsoo Kim, Jeroen Kneppers, Simon Linder, Suzan Stelloo, Cor Lieftink, Michiel S. van der Heijden, Matti Nykter, Vincent van der Noort, Joyce Sanders, Ben Morris, Guido Jenster, Geert JLH van Leenders, Mark Pomerantz, Matthew L. Freedman, Roderick L. Beijersbergen, Alfonso Urbanucci, Lodewyk Wessels, Peter S. Nelson, Eva Corey, Stefan Prekovic, Wilbert Zwart, Andries M. Bergman
Cell Reports Medicine, 2025
Androgen receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase 2 clinical trial, we epigenetically profile enhancer/promoter activities with acetylation of lysine residue 27 on histone 3 (H3K27ac) chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identify a distinct subset of H3K27ac-differentially marked regions that are associated with treatment responsiveness, which we successfully validate in mCRPC patient-derived xenograft (PDX) models. In silico analyses reveal histone deacetylase (HDAC)3 to critically drive resistance to hormonal interventions, which we validate in vitro. Critically, we identify the pan-HDAC inhibitor vorinostat to be effective in decreasing tumor cell proliferation, both in vitro and in vivo. Moreover, we uncover evidence for HDAC3 working together with glucocorticoid receptor (GR) as a potential mechanism for this therapeutic effect. These findings demonstrate the rationale for therapeutic strategies including HDAC inhibitors to improve patient outcome in advanced stages of mCRPC. - Zincore, an atypical coregulator, binds zinc finger transcription factors to control gene expression
Daniëlle Bianchi, Razvan Borza, Erica De Zan, Guizela Huelsz-Prince, Sebastian Gregoricchio, Marleen Dekker, Alex Fish, Abdelghani Mazouzi, Lona J. Kroese, Simon Linder, Miguel Hernandez-Quiles, Michiel Vermeulen, Patrick H. N. Celie, Paul Krimpenfort, Ji-Ying Song, Wilbert Zwart, Lodewyk Wessels, Sebastian M. B. Nijman, Anastassis Perrakis, Thijn R. Brummelkamp
Science, 2025 - Comprehensive functional annotation of ESR1-driven enhancers in breast cancer reveals hierarchical activity independent of genomic and epigenomic contexts
Yanis Zekri, Sebastian Gregoricchio, Elif Yapıcı, Chia-Chi Flora Huang, Tunç Morova, Umut Berkay Altıntaş, Gozde Korkmaz, Nathan A. Lack, Wilbert Zwart
Genome Research, 2025 - Targeting DOT1L and EZH2 synergizes in breaking the germinal center identity of diffuse large B-cell lymphoma
Camiel Göbel, Rachele Niccolai, Marnix Hugo Philip de Groot, Jayashree Jayachandran, Joleen Traets, Daan Juri Kloosterman, Sebastian Gregoricchio, Ben Morris, Maaike Kreft, Ji-Ying Song, Leyla Azarang, Eirini Kasa, Nienke Oskam, Daniel de Groot, Liesbeth Hoekman, Onno Bleijerveld, Marie José Kersten, Muhammad Assad Aslam, Fred van Leeuwen, Heinz Jacobs
Blood, 2025 - Chromatin context-dependent effects of epigenetic drugs on CRISPR-Cas9 editing
Ruben Schep, Max Trauernicht, Xabier Vergara, Anoek Friskes, Ben Morris, Sebastian Gregoricchio, Stefano G Manzo, Wilbert Zwart, Roderick L Beijersbergen, René H Medema, Bas van Steensel
Nucleic Acids Research, 2024 - Estrogen receptor 1 chromatin profiling in human breast tumors reveals high inter-patient heterogeneity with enrichment of risk SNPs and enhancer activity at most-conserved regions
Stacey E.P. Joosten, Sebastian Gregoricchio, Suzan Stelloo, Elif Yapıcı, Chia-Chi Flora Huang, Kerim Yavuz, Maria Donaldson Collier, Tunç Morova, Umut Berkay Altintaş, Yongsoo Kim, Sander Canisius, Cathy B. Moelans, Paul J. van Diest, Gozde Korkmaz, Nathan A. Lack, Michiel Vermeulen, Sabine C. Linn, Wilbert Zwart
Genome Research, 2024 - PAXIP1 and STAG2 converge to maintain 3D genome architecture and facilitate promoter/enhancer contacts to enable stress hormone-dependent transcription
Isabel Mayayo-Peralta, Sebastian Gregoricchio, Karianne Schuurman, Selçuk Yavuz, Anniek Zaalberg, Aleksandar Kojic, Nina Abbott, Bart Geverts, Suzanne Beerthuijzen, Joseph Siefert, Tesa M Severson, Martijn van Baalen, Liesbeth Hoekman, Cor Lieftink, Maarten Altelaar, Roderick L Beijersbergen, Adriaan B Houtsmuller, Stefan Prekovic, Wilbert Zwart
Nucleic Acids Research, 2023 - FANCA deficiency promotes leukaemic progression by allowing the emergence of cells carrying oncogenic driver mutations
Patrycja Pawlikowska, Laure Delestré, Sebastian Gregoricchio, Alessia Oppezzo, Michela Esposito, M’ Boyba Diop, Filippo Rosselli, Christel Guillouf
Oncogene, 2023 - SnHiC: A complete and simplified snakemake pipeline for grouped Hi-C data analysis
Sebastian Gregoricchio, Wilbert Zwart
Bioinformatics Advances, 2023 - HDAC1 and PRC2 mediate combinatorial control in SPI1/PU.1-dependent gene repression in murine erythroleukaemia
Sebastian Gregoricchio, Lélia Polit, Michela Esposito, Jérémy Berthelet, Laure Delestré, Emilie Evanno, M’Boyba Diop, Isabelle Gallais, Hanna Aleth, Mathilde Poplineau, Wilbert Zwart, Frank Rosenbauer, Fernando Rodrigues-Lima, Estelle Duprez, Valentina Boeva, Christel Guillouf
Nucleic Acids Research, 2022 - CHIPIN: ChIP-seq inter-sample normalization based on signal invariance across transcriptionally constant genes
Lélia Polit, Gwenneg Kerdivel, Sebastian Gregoricchio, Michela Esposito, Christel Guillouf, Valentina Boeva
BMC Bioinformatics, 2021
