CeMM Adjunct Principal Investigator
Pediatric leukemia biology
We are a team of molecular and computational biologists working at the interface between chromatin biology, genome editing and cancer. We are particularly interested in understanding aspects of gene regulation in the context of pediatric leukemia and other malignancies. Our research is focused on two main areas:
Non-coding regulatory sequences in leukemia
Functional non-coding regions such as enhancers and insulators play an essential role in the regulation of cell type-specific gene expression programs, and mutations at non-coding elements can drive observable phenotypic changes comparable to those driven by mutations at coding sequences (see Seruggia et al. 2015; Seruggia et al. 2020). However, due to lack of appropriate technology, just a limited number of disease-related regulatory sequences have been described, leaving many potential targets of therapy to be discovered. For these reasons, our goal is to investigate the contribution of non-coding sequences and 3D genome structure in cancer. We focus on leukemia development and drug resistance. What is the role of enhancers in the acquisition of drug resistance? How chromatin topology affects gene expression in leukemia? What is the effect of sequence variation at enhancers whose mutation is associated with leukemia? We use epi/genome editing (CRISPR, CRISPRi, CRISPRa), chromatin profiling (ChIP-seq, Cut and Run, ATAC-seq) and computational biology to answer these questions.
TFIID/SAGA components as targets in pediatric cancer
We previously reported a connection between two chromatin modifiers of the SAGA complex and self-renewal in mouse embryonic stem cells (see Seruggia et al 2019). We discovered that loss of Taf5l and Taf6l in mESCs results in a dramatic reduction in c-Myc expression at the RNA and protein levels. However, the functions of Taf5l and Taf6l in mESCs and other cell types, as well as their mechanism of action, remain unexplored. How do Taf5l and Taf6l control c-Myc expression and stem cell identity? Are these factors required in other types of stem cells, i.e. adult hematopoietic stem cells? Can we harness vulnerabilities within the TFIID and SAGA members to treat MYC-driven malignancies? We use mouse models, genomics and genome editing to answer these questions.
Davide Seruggia obtained a degree in biotechnology at the University of Milano-Bicocca (Italy) in 2010, and a PhD in molecular biology at the National Center for Biotechnology (CNB-CSIC) in Madrid (Spain) in 2014. During his PhD under the supervision of Lluis Montoliu, he focused on non-coding DNA regulatory sequences of pigmentation genes and generated several mouse lines carrying deletions of selected enhancers. Analysis of these mice highlighted the relevance of noncoding elements in regulating patterns of gene expression. In 2015, he joined the laboratory of Stuart H. Orkin at Boston Children’s Hospital, where he trained in hematology, stem cell biology, and genomics. In Boston, Seruggia used genomics and genome editing to explore the role of epigenetic factors, chromatin modifiers, and transcriptional coactivators in the context of mouse embryonic stem cells, and generated a series of mouse models to study how chromatin modifiers control hematopoiesis, erythropoiesis, and the expression of globin genes. In 2019, he was promoted to instructor in pediatrics at Harvard Medical School and attracted funding from the WES Foundation and Pedals for Pediatrics. In 2020, he was awarded an ERC Starting Grant and started his independent career in 2021, when he joined St. Anna Children’s Cancer Research Institute as principal investigator and CeMM as adjunct principal investigator.
Mehta S et al. Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells. Cell Chem Biol. 2022 Aug 18;29(8):1273-1287.e8. (abstract)
Seruggia D, Oti M, Tripathi P, Canver MC, LeBlanc L, Di Giammartino DC, Bullen MJ, Nefzger CM, Sun YBY, Farouni R, Polo JM, Pinello L, Apostolou E, Kim J, Orkin SH, Das PP. TAF5L and TAF6L Maintain Self-Renewal of Embryonic Stem Cells via the MYC Regulatory Network. Mol Cell. 2019 Jun 20;74(6):1148-1163.e7. (abstract)
Sher F, Hossain M, Seruggia D, Schoonenberg VAC, Yao Q, Cifani P, Dassama LMK, Cole MA, Ren C, Vinjamur DS, Macias-Trevino C, Luk K, McGuckin C, Schupp PG, Canver MC, Kurita R, Nakamura Y, Fujiwara Y, Wolfe SA, Pinello L, Maeda T, Kentsis A, Orkin SH, Bauer DE. Rational targeting of a NuRD subcomplex guided by comprehensive in situ mutagenesis. Nat Genet. 2019 Jul;51(7):1149-1159. (abstract)
Debruyne DN, Dries R, Sengupta S, Seruggia D, Gao Y, Sharma B, Huang H, Moreau L, McLane M, Day DS, Marco E, Chen T, Gray NS, Wong KK, Orkin SH, Yuan GC, Young RA, George RE. BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells. Nature. 2019 Aug;572(7771):676-680. (abstract)
Cai W, Huang J, Zhu Q, Li BE, Seruggia D, Zhou P, Nguyen M, Fujiwara Y, Xie H, Yang Z, Hong D, Ren P, Xu J, Pu WT, Yuan GC, Orkin SH. Enhancer dependence of cell-type-specific gene expression increases with developmental age. Proc Natl Acad Sci U S A. 2020 Sep 1;117(35):21450-21458. (abstract)
Seruggia D, Fernández A, Cantero M, Fernández-Miñán A, Gomez-Skarmeta JL, Pelczar P, Montoliu L. Boundary sequences flanking the mouse tyrosinase locus ensure faithful pattern of gene expression. Sci Rep. 2020 Sep 23;10(1):15494. (abstract)
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