Davide Seruggia

We are a team of molecular and computational biologists working at the interface of chromatin biology, genome editing, and cancer research. We are particularly interested in understanding fundamental aspects of gene regulation in the context of pediatric leukemia and other hematologic malignancies. Our research focuses on two main areas:

Non-coding regulatory sequences in leukemia

Non-coding functional regions such as enhancers and insulators are essential for the regulation of cell type-specific gene expression. Mutations in these non-coding elements can drive phenotypic changes comparable to those caused by mutations in coding sequences (see Seruggia et al. 2015; Seruggia et al. 2020). However, due to limitations in current genomic technologies, relatively few disease-associated regulatory sequences have been identified—leaving many potential therapeutic targets undiscovered.

Our goal is to investigate the contribution of non-coding DNA sequences and 3D genome architecture to cancer development. We focus particularly on leukemia progression and drug resistance mechanisms. Key questions we explore include:

• What role do enhancers play in the acquisition of drug resistance?
• How does chromatin topology influence gene expression in leukemia?
• What is the effect of sequence variation in enhancers whose mutation is linked to leukemia?

To address these questions, we combine epigenome and genome editing (e.g., CRISPR, CRISPRi, CRISPRa), chromatin profiling (ChIP-seq, Cut&Run, ATAC-seq), and computational biology.

TFIID/SAGA components as targets in pediatric cancer

We previously reported a functional link between chromatin regulators in the SAGA complex and self-renewal in mouse embryonic stem cells (mESCs) (see Seruggia et al. 2019). We found that loss of Taf5l and Taf6l in mESCs leads to a significant reduction in c-Myc expression at both the RNA and protein levels. However, the biological roles and molecular mechanisms of Taf5l and Taf6l in mESCs and other cell types remain largely unexplored.

Our ongoing research seeks to address the following:

• How do Taf5l and Taf6l regulate c-Myc expression and stem cell identity?
• Are these chromatin factors required in other types of stem cells, such as adult hematopoietic stem cells?
• Can we exploit vulnerabilities in TFIID and SAGA complex members to develop targeted therapies for MYC-driven pediatric cancers?

We use mouse models, functional genomics, and genome editing technologies to investigate 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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