Honors & Awards


  • Marie Skłodowska-Curie Postdoctoral Fellow, European Commission (2018)
  • ARC Foundation Postdoctoral Fellow, Fondation ARC pour la recherche sur le cancer (2017)
  • EMBO Short-Term Fellow, European Molecular Biology Organization (2014)
  • Marie Skłodowska-Curie Ph.D. fellow, European Commission (2012)
  • Erasmus Mundus exchange scholar, European Commission (2011)

Professional Education


  • Ph.D., Universidad Autónoma de Madrid, Molecular Biosciences (2016)
  • M.Sc., Università di Bologna, Bioinformatics (2012)
  • B.Sc., Università degli Studi di Padova, Biology (2010)

Stanford Advisors


Lab Affiliations


All Publications


  • HIRA-dependent boundaries between H3 variants shape early replication in mammals. Molecular cell Gatto, A., Forest, A., Quivy, J., Almouzni, G. 2022

    Abstract

    The lack of a consensus DNA sequence defining replication origins in mammals has led researchers to consider chromatin as a means to specify these regions. However, to date, there is no mechanistic understanding of how this could be achieved and maintained given that nucleosome disruption occurs with each fork passage and with transcription. Here, by genome-wide mapping of the de novo deposition of the histone variants H3.1 and H3.3 in human cells during S phase, we identified how their dual deposition mode ensures a stable marking with H3.3 flanked on both sides by H3.1. These H3.1/H3.3 boundaries correspond to the initiation zones of early origins. Loss of the H3.3 chaperone HIRA leads to the concomitant disruption of H3.1/H3.3 boundaries and initiation zones. We propose that the HIRA-dependent deposition of H3.3 preserves H3.1/H3.3 boundaries by protecting them from H3.1 invasion linked to fork progression, contributing to a chromatin-based definition of early replication zones.

    View details for DOI 10.1016/j.molcel.2022.03.017

    View details for PubMedID 35381196

  • CENP-A overexpression promotes distinct fates in human cells, depending on p53 status COMMUNICATIONS BIOLOGY Jeffery, D., Gatto, A., Podsypanina, K., Renaud-Pageot, C., Landete, R., Bonneville, L., Dumont, M., Fachinetti, D., Almouzni, G. 2021; 4 (1): 417

    Abstract

    Tumour evolution is driven by both genetic and epigenetic changes. CENP-A, the centromeric histone H3 variant, is an epigenetic mark that directly perturbs genetic stability and chromatin when overexpressed. Although CENP-A overexpression is a common feature of many cancers, how this impacts cell fate and response to therapy remains unclear. Here, we established a tunable system of inducible and reversible CENP-A overexpression combined with a switch in p53 status in human cell lines. Through clonogenic survival assays, single-cell RNA-sequencing and cell trajectory analysis, we uncover the tumour suppressor p53 as a key determinant of how CENP-A impacts cell state, cell identity and therapeutic response. If p53 is functional, CENP-A overexpression promotes senescence and radiosensitivity. Surprisingly, when we inactivate p53, CENP-A overexpression instead promotes epithelial-mesenchymal transition, an essential process in mammalian development but also a precursor for tumour cell invasion and metastasis. Thus, we uncover an unanticipated function of CENP-A overexpression to promote cell fate reprogramming, with important implications for development and tumour evolution.

    View details for DOI 10.1038/s42003-021-01941-5

    View details for Web of Science ID 000635193900005

    View details for PubMedID 33772115

    View details for PubMedCentralID PMC7997993

  • AsiDNA Is a Radiosensitizer with no Added Toxicity in Medulloblastoma Pediatric Models CLINICAL CANCER RESEARCH Ferreira, S., Foray, C., Gatto, A., Larcher, M., Heinrich, S., Lupu, M., Mispelter, J., Boussin, F. D., Pouponnot, E., Dutreix, M. 2020; 26 (21): 5735-5746

    Abstract

    Medulloblastoma is an important cause of mortality and morbidity in pediatric oncology. Here, we investigated whether the DNA repair inhibitor, AsiDNA, could help address a significant unmet clinical need in medulloblastoma care, by improving radiotherapy efficacy without increasing radiation-associated toxicity.To evaluate the brain permeability of AsiDNA upon systemic delivery, we intraperitoneally injected a fluorescence form of AsiDNA in models harboring brain tumors and in models still in development. Studies evaluated toxicity associated with combination of AsiDNA with radiation in the treatment of young developing animals at subacute levels, related to growth and development, and at chronic levels, related to brain organization and cognitive skills. Efficacy of the combination of AsiDNA with radiation was tested in two different preclinical xenografted models of high-risk medulloblastoma and in a panel of medulloblastoma cell lines from different molecular subgroups and TP53 status. Role of TP53 on the AsiDNA-mediated radiosensitization was analyzed by RNA-sequencing, DNA repair recruitment, and cell death assays.Capable of penetrating young brain tissues, AsiDNA showed no added toxicity to radiation. Combination of AsiDNA with radiotherapy improved the survival of animal models more efficiently than increasing radiation doses. Medulloblastoma radiosensitization by AsiDNA was not restricted to a specific molecular group or status of TP53. Molecular mechanisms of AsiDNA, previously observed in adult malignancies, were conserved in pediatric models and resembled dose increase when combined with irradiation.Our results suggest that AsiDNA is an attractive candidate to improve radiotherapy in medulloblastoma, with no indication of additional toxicity in developing brain tissues.

    View details for DOI 10.1158/1078-0432.CCR-20-1729

    View details for Web of Science ID 000584529900021

    View details for PubMedID 32900798

  • Histone supply: Multitiered regulation ensures chromatin dynamics throughout the cell cycle JOURNAL OF CELL BIOLOGY Mendiratta, S., Gatto, A., Almouzni, G. 2019; 218 (1): 39-54

    Abstract

    As the building blocks of chromatin, histones are central to establish and maintain particular chromatin states associated with given cell fates. Importantly, histones exist as distinct variants whose expression and incorporation into chromatin are tightly regulated during the cell cycle. During S phase, specialized replicative histone variants ensure the bulk of the chromatinization of the duplicating genome. Other non-replicative histone variants deposited throughout the cell cycle at specific loci use pathways uncoupled from DNA synthesis. Here, we review the particular dynamics of expression, cellular transit, assembly, and disassembly of replicative and non-replicative forms of the histone H3. Beyond the role of histone variants in chromatin dynamics, we review our current knowledge concerning their distinct regulation to control their expression at different levels including transcription, posttranscriptional processing, and protein stability. In light of this unique regulation, we highlight situations where perturbations in histone balance may lead to cellular dysfunction and pathologies.

    View details for DOI 10.1083/jcb.201807179

    View details for Web of Science ID 000455041500008

    View details for PubMedID 30257851

    View details for PubMedCentralID PMC6314538

  • High-resolution visualization of H3 variants during replication reveals their controlled recycling NATURE COMMUNICATIONS Clement, C., Orsi, G. A., Gatto, A., Boyarchuk, E., Forest, A., Hajj, B., Mine-Hattab, J., Garnier, M., Gurard-Levin, Z. A., Quivy, J., Almouzni, G. 2018; 9: 3181

    Abstract

    DNA replication is a challenge for the faithful transmission of parental information to daughter cells, as both DNA and chromatin organization must be duplicated. Replication stress further complicates the safeguard of epigenome integrity. Here, we investigate the transmission of the histone variants H3.3 and H3.1 during replication. We follow their distribution relative to replication timing, first in the genome and, second, in 3D using super-resolution microscopy. We find that H3.3 and H3.1 mark early- and late-replicating chromatin, respectively. In the nucleus, H3.3 forms domains, which decrease in density throughout replication, while H3.1 domains increase in density. Hydroxyurea impairs local recycling of parental histones at replication sites. Similarly, depleting the histone chaperone ASF1 affects recycling, leading to an impaired histone variant landscape. We discuss how faithful transmission of histone variants involves ASF1 and can be impacted by replication stress, with ensuing consequences for cell fate and tumorigenesis.

    View details for DOI 10.1038/s41467-018-05697-1

    View details for Web of Science ID 000441157600016

    View details for PubMedID 30093638

    View details for PubMedCentralID PMC6085313

  • Neurogenesis: Regulation by Alternative Splicing and Related Posttranscriptional Processes NEUROSCIENTIST Lara-Pezzi, E., Desco, M., Gatto, A., Victoria Gomez-Gaviro, M. 2017; 23 (5): 466-477

    Abstract

    The complexity of the mammalian brain requires highly specialized protein function and diversity. As neurons differentiate and the neuronal circuitry is established, several mRNAs undergo alternative splicing and other posttranscriptional changes that expand the variety of protein isoforms produced. Recent advances are beginning to shed light on the molecular mechanisms that regulate isoform switching during neurogenesis and the role played by specific RNA binding proteins in this process. Neurogenesis and neuronal wiring were recently shown to also be regulated by RNA degradation through nonsense-mediated decay. An additional layer of regulatory complexity in these biological processes is the interplay between alternative splicing and long noncoding RNAs. Dysregulation of posttranscriptional regulation results in defective neuronal differentiation and/or synaptic connections that lead to neurodevelopmental and psychiatric disorders.

    View details for DOI 10.1177/1073858416678604

    View details for Web of Science ID 000412270000008

    View details for PubMedID 27837180

  • The Calcineurin Variant CnA beta 1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation CELL CHEMICAL BIOLOGY Gomez-Salinero, J. M., Lopez-Olaneta, M. M., Ortiz-Sanchez, P., Larrasa-Alonso, J., Gatto, A., Felkin, L. E., Barton, P. R., Navarro-Lerida, I., del Pozo, M., Garcia-Pavia, P., Sundararaman, B., Giovinazo, G., Yeo, G. W., Lara-Pezzi, E. 2016; 23 (11): 1372-1382

    Abstract

    Embryonic stem cells (ESC) have the potential to generate all the cell lineages that form the body. However, the molecular mechanisms underlying ESC differentiation and especially the role of alternative splicing in this process remain poorly understood. Here, we show that the alternative splicing regulator MBNL1 promotes generation of the atypical calcineurin Aβ variant CnAβ1 in mouse ESCs (mESC). CnAβ1 has a unique C-terminal domain that drives its localization mainly to the Golgi apparatus by interacting with Cog8. CnAβ1 regulates the intracellular localization and activation of the mTORC2 complex. CnAβ1 knockdown results in delocalization of mTORC2 from the membrane to the cytoplasm, inactivation of the AKT/GSK3β/β-catenin signaling pathway, and defective mesoderm specification. In summary, here we unveil the structural basis for the mechanism of action of CnAβ1 and its role in the differentiation of mESCs to the mesodermal lineage.

    View details for DOI 10.1016/j.chembiol.2016.09.010

    View details for Web of Science ID 000388373200010

    View details for PubMedID 27746127

  • FineSplice, enhanced splice junction detection and quantification: a novel pipeline based on the assessment of diverse RNA-Seq alignment solutions NUCLEIC ACIDS RESEARCH Gatto, A., Torroja-Fungairino, C., Mazzarotto, F., Cook, S. A., Barton, P. R., Sanchez-Cabo, F., Lara-Pezzi, E. 2014; 42 (8): e71

    Abstract

    Alternative splicing is the main mechanism governing protein diversity. The recent developments in RNA-Seq technology have enabled the study of the global impact and regulation of this biological process. However, the lack of standardized protocols constitutes a major bottleneck in the analysis of alternative splicing. This is particularly important for the identification of exon-exon junctions, which is a critical step in any analysis workflow. Here we performed a systematic benchmarking of alignment tools to dissect the impact of design and method on the mapping, detection and quantification of splice junctions from multi-exon reads. Accordingly, we devised a novel pipeline based on TopHat2 combined with a splice junction detection algorithm, which we have named FineSplice. FineSplice allows effective elimination of spurious junction hits arising from artefactual alignments, achieving up to 99% precision in both real and simulated data sets and yielding superior F1 scores under most tested conditions. The proposed strategy conjugates an efficient mapping solution with a semi-supervised anomaly detection scheme to filter out false positives and allows reliable estimation of expressed junctions from the alignment output. Ultimately this provides more accurate information to identify meaningful splicing patterns. FineSplice is freely available at https://sourceforge.net/p/finesplice/.

    View details for DOI 10.1093/nar/gku166

    View details for Web of Science ID 000336092300010

    View details for PubMedID 24574529

    View details for PubMedCentralID PMC4005686

  • The Alternative Heart: Impact of Alternative Splicing in Heart Disease JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Lara-Pezzi, E., Gomez-Salinero, J., Gatto, A., Garcia-Pavia, P. 2013; 6 (6): 945-955

    Abstract

    Alternative splicing is the main driver of protein diversity and allows the production of different proteins from each gene in the genome. Changes in exon exclusion, intron retention or the use of alternative splice sites can alter protein structure, localisation, regulation and function. In the heart, alternative splicing of sarcomeric genes, ion channels and cell signalling proteins can lead to cardiomyopathies, arrhythmias and other pathologies. Also, a number of inherited conditions and heart-related diseases develop as a result of mutations affecting splicing. Here, we review the impact that changes in alternative splicing have on individual genes and on whole biological processes associated with heart disease. We also discuss promising therapeutic tools based on the manipulation of alternative splicing.

    View details for DOI 10.1007/s12265-013-9482-z

    View details for Web of Science ID 000327459200007

    View details for PubMedID 23775418