Elisa Oricchio

De novo design of protein interactions with learned surface fingerprints

Michael Bronstein, Stephen M Buckley, Bruno Emanuel Ferreira De Sousa Correia, Beat Fierz, Pablo Gainza Cirauqui, Sandrine Madeleine Suzanne Georgeon, Casper Alexander Goverde, Zander Harteveld, Anthony Marchand, Jane Marsden, Dongchun Ni, Elisa Oricchio, Aaron Simone Petruzzella, Charlène Mireille Raymonde Raclot, Stéphane Rosset, Andreas Scheck, Henning Paul-Julius Stahlberg, Freyr Sverrisson, Alexandra Teslenko, Didier Trono, Priscilla Turelli, Alexandra Krina Van Hall-Beauvais, Sarah Wehrle

Physical interactions between proteins are essential for most biological processes governing life. However, the molecular determinants of such interactions have been challenging to understand, even as genomic, proteomic and structural data increase. This knowledge gap has been a major obstacle for the comprehensive understanding of cellular protein–protein interaction networks and for the de novo design of protein binders that are crucial for synthetic biology and translational applications. Here we use a geometric deep-learning framework operating on protein surfaces that generates fingerprints to describe geometric and chemical features that are critical to drive protein–protein interactions10. We hypothesized that these fingerprints capture the key aspects of molecular recognition that represent a new paradigm in the computational design of novel protein interactions. As a proof of principle, we computationally designed several de novo protein binders to engage four protein targets: SARS-CoV-2 spike, PD-1, PD-L1 and CTLA-4. Several designs were experimentally optimized, whereas others were generated purely in silico, reaching nanomolar affinity with structural and mutational characterization showing highly accurate predictions. Overall, our surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling an approach for the de novo design of protein interactions and, more broadly, of artificial proteins with function.

2023

Whole-genome doubling drives oncogenic loss of chromatin segregation

Giovanni Ciriello, Juan Diaz Miyar, Natalya Katanayeva, Ruxandra-Andreea Lambuta, Elisa Oricchio

Whole-genome doubling (WGD) is a recurrent event in human cancers and it promotes chromosomal instability and acquisition of aneuploidies(1-8). However, the three-dimensional organization of chromatin in WGD cells and its contribution to oncogenic phenotypes are currently unknown. Here we show that in p53-deficient cells, WGD induces loss of chromatin segregation (LCS). This event is characterized by reduced segregation between short and long chromosomes, A and B subcompartments and adjacent chromatin domains. LCS is driven by the downregulation of CTCF and H3K9me3 in cells that bypassed activation of the tetraploid checkpoint. Longitudinal analyses revealed that LCS primes genomic regions for subcompartment repositioning in WGD cells. This results in chromatin and epigenetic changes associated with oncogene activation in tumours ensuing from WGD cells. Notably, subcompartment repositioning events were largely independent of chromosomal alterations, which indicates that these were complementary mechanisms contributing to tumour development and progression. Overall, LCS initiates chromatin conformation changes that ultimately result in oncogenic epigenetic and transcriptional modifications, which suggests that chromatin evolution is a hallmark of WGD-driven cancer.

NATURE PORTFOLIO2023

Cathepsin inhibitors and uses thereof

Elena Battistello, Elisa Oricchio, Luc Reymond

The present invention relates to new agents and compositions thereof useful for anti-cancer and immunological disorder therapy and uses thereof. The invention further relates to a method of identifying agents useful in the potentiation of immunotherapy, in particular Cathepsin S inhibitors.

2021

Genomic studies indicate a novel combination therapy for follicular lymphoma COMMENT

Elisa Oricchio

Follicular lymphoma (FL) is an incurable form of B-cell lymphoma. Genomic alterations that inactivate RB signaling are surprisingly common in indolent FL. We show that FLs that are positive for phosphorylated RB respond to dual CDK4/BCL2 inhibition. Our results imply that RB phosphorylation identifies patients likely to benefit from such dual intervention.

TAYLOR & FRANCIS INC2021

Histone acetylation dynamics modulates chromatin conformation and allele-specific interactions at oncogenic loci

Giovanni Ciriello, Natalya Katanayeva, Ruxandra-Andreea Lambuta, Elisa Oricchio, Stephanie Jocelyne Sungalee

In cancer cells, enhancer hijacking mediated by chromosomal alterations and/or increased deposition of acetylated histone H3 lysine 27 (H3K27ac) can support oncogene expression. However, how the chromatin conformation of enhancer-promoter interactions is affected by these events is unclear. In the present study, by comparing chromatin structure and H3K27ac levels in normal and lymphoma B cells, we show that enhancer-promoter-interacting regions assume different conformations according to the local abundance of H3K27ac. Genetic or pharmacological depletion of H3K27ac decreases the frequency and the spreading of these interactions, altering oncogene expression. Moreover, enhancer hijacking mediated by chromosomal translocations influences the epigenetic status of the regions flanking the breakpoint, prompting the formation of distinct intrachromosomal interactions in the two homologous chromosomes. These interactions are accompanied by allele-specific gene expression changes. Overall, our work indicates that H3K27ac dynamics modulates interaction frequency between regulatory regions and can lead to allele-specific chromatin configurations to sustain oncogene expression. Enhancer-promoter three-dimensional interactions at oncogenic loci are modulated by H3K27ac dynamics. Enhancer hijacking mediated by chromosomal translocations leads to distinct chromatin states, intrachromosomal interactions and allele-specific gene expression.

2021

Systematic inference and comparison of multi-scale chromatin sub-compartments connects spatial organization to cell phenotypes

Giovanni Ciriello, Marco Mina, Elisa Oricchio, Stephanie Jocelyne Sungalee

Chromatin compartmentalization reflects biological activity. However, inference of chromatin sub-compartments and compartment domains from chromosome conformation capture (Hi-C) experiments is limited by data resolution. As a result, these have been characterized only in a few cell types and systematic comparisons across multiple tissues and conditions are missing. Here, we present Calder, an algorithmic approach that enables the identification of multi-scale sub-compartments at variable data resolution. Calder allows to infer and compare chromatin sub-compartments and compartment domains in >100 cell lines. Our results reveal sub-compartments enriched for poised chromatin states and undergoing spatial repositioning during lineage differentiation and oncogenic transformation. Computational algorithms to infer chromatin sub-compartments and compartment domains require high-resolution Hi-C maps. Here the authors present Calder, an algorithm that can infer sub-compartments and compartment domains with variable resolution Hi-C data, and they apply it to more than a hundred Hi-C experiments to study sub-compartment repositioning.

NATURE RESEARCH2021

Cathepsin S Regulates Antigen Processing and T Cell Activity in Non-Hodgkin Lymphoma

Elena Battistello, Giovanni Ciriello, George Coukos, Elie Charles Eugène Dheilly, Bruno Emanuel Ferreira De Sousa Correia, Natalya Katanayeva, Marco Mina, Elisa Oricchio, Julien Racle, Jessica Sordet-Dessimoz, Stephanie Jocelyne Sungalee, Sarah Wehrle

Genomic alterations in cancer cells can influence the immune system to favor tumor growth. In non-Hodgkin lymphoma, physiological interactions between B cells and the germinal center microenvironment are coopted to sustain cancer cell proliferation. We found that follicular lymphoma patients harbor a recurrent hotspot mutation targeting tyrosine 132 (Y132D) in cathepsin S (CTSS) that enhances protein activity. CTSS regulates antigen processing and CD4+ and CD8+ T cell-mediated immune responses. Loss of CTSS activity reduces lymphoma growth by limiting communication with CD4+ T follicular helper cells while inducing antigen diversification and activation of CD8+ T cells. Overall, our results suggest that CTSS inhibition has non-redundant therapeutic potential to enhance anti-tumor immune responses in indolent and aggressive lymphomas.

2020

De novo protein design enables the precise induction of RSV-neutralizing antibodies

Luciano Andres Abriata, Jaume Bonet Martinez, Patricia Corthésy Henrioud, Elie Charles Eugène Dheilly, Bruno Emanuel Ferreira De Sousa Correia, Sandrine Madeleine Suzanne Georgeon, Elisa Oricchio, Stéphane Rosset, Fabian Sesterhenn, Mélanie Evelyne Villard, Sabrina Susan Vollers, Yimeng Wang, Che Yang

De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a protein design algorithm called TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. In both mice and nonhuman primates, cocktails of three de novo-designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused preexisting antibody responses toward defined neutralization epitopes. Overall, our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs.

2020