Biology subjects

Boccalatte, F.

Publications and source records attributed to Boccalatte, F..

7 recordsLinked to original sources

bioRxiv2026

SMARCA4 MUTATIONS PROMOTE CHEMOTHERAPY RESISTANCE IN T-ACUTE LYMPHOBLASTIC LEUKEMIA THROUGH ALTERED CHROMATIN REMODELING AT AP1-ASSOCIATED REGULATORY REGIONS

Chromatin remodelers play a critical role in orchestrating chemotherapy responses in cancer cells. Components of the SWI/SNF complex are frequently mutated across cancer types, with the ATPase subunit SMARCA4 among the most commonly altered. In T-cell acute lymphoblastic leukemia (T-ALL), however, SMARCA4 mutations are rare at diagnosis but enriched in relapse samples, suggesting a potential role in therapy resistance. Using isogenic T-ALL cell lines with or without SMARCA4 mutations, we show that mutant SMARCA4 confers resistance to a broad range of chemotherapeutic agents. By combining ATAC-seq and RNA-seq, we demonstrate that SMARCA4-mutant cells display an attenuated transcriptional response to chemotherapy accompanied by impaired remodeling of AP-1-associated regulatory regions linked to stress response. These cells downregulate stress-related genes while maintaining expression programs associated with cellular fitness. Pharmacological inhibition of AP-1 phenocopies this response, further supporting a functional link between SWI/SNF-mediated remodeling at AP-1-associated regulatory regions, AP-1 activity, and chemotherapy sensitivity. Together, our findings indicate that SWI/SNF-mediated remodeling of these regions contributes to an effective chemotherapy-induced stress response, and that its failure provides T-ALL cells with a survival

cancer biology↗

bioRxiv2026

Characterization of Human Ectocentromeric Sites.

Centromeres are composed of DNA repeats within chromosomes primary constriction. CENP-B is the only centromeric protein known to bind a specific motif, the CENP-B box, promoting kinetochore stability. We recently uncovered degenerate CENP-B binding motifs outside centromeres, whose position and orientation defines chromosome specific banding patterns. Here, we leveraged telomere-to-telomere assemblies to map conservation of these ectocentromeric sequences (ECS) across hundreds of haplotypes. We found strong negative selection acting on their occurrence along chromosome arms, implying functional constraints incompatible with stochastic drift. We classified four categories: (i) ECSs that lack CENP-B binding ([~]84%); (ii) ECSs bound by CENP-B ([~]10%); (iii) ECSs near CENP-B-enriched accessible chromatin ([~]6%); (iv) we further identified [~]700 CENP-B binding sites outside centromeres without CENP-B boxes. Integrating chromatin conformation capture (HiC), neocentromeres and meiotic recombination mapping with CENP-B CUT&RUN, methylation and ATAC-seq data, we found heterogenous functionalities driven by distance-dependent enrichment and local contacts of boxes in inverted orientation on the same strand, analogous to ALU repeats affecting topological folding. CENP-B knockdown significantly reduced neighboring gene expression, revealing a moonlighting regulatory role outside centromeres. Our findings characterizes human ectocentromeric sites as evolutionarily constrained and functionally heterogeneous elements along chromosome arms with context-dependent roles in chromatin state. Graphical AbstractEctocentromeric sites exhibit heterogeneous CENP-B occupancy and context-dependent chromatin functions. Ectocentromeric sequences (ECSs) along chromosome arms fall into four categories: (i) CENP-B box motifs alone, lacking protein binding, embedded within repressed or boundary chromatin and contributing to TAD organization. Motifs with opposite orientation (forward and reverse complement) paired on the same strand may further promote self-complementary chromatin contacts analogous to Alu inverted repeats, reshaping topology with long-range looping contacts; (ii/iii) ECSs bound by CENP-B protein, associated with specific open chromatin state downstream of H3K27me3-marked compacted chromatin that modulate local accessibility and gene expression; and (iv) CENP-B binding peaks lacking a canonical box motif, located proximal to transcription start sites and linked to active gene expression. Together, ectocentromeric sites represent functionally heterogeneous elements with context-dependent roles spanning chromosome architecture, chromatin state, and transcription regulation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/728588v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1683fb7org.highwire.dtl.DTLVardef@12f1c9dorg.highwire.dtl.DTLVardef@1ffc699org.highwire.dtl.DTLVardef@14790dd_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2025

TASC: A transcriptome-driven machine learning classifier to explore molecular heterogeneity and relapse-associated programs in T-cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia is a biologically heterogeneous malignancy characterized by diverse transcriptional and genomic alterations. Recent studies have defined a set of recurrent molecular subtypes associated with distinct differentiation stages and clinical outcomes. However, no unified framework currently exists for assigning these subtypes in a standardized and accessible manner. Existing approaches often rely on mutation or fusion detection and may overlook broader transcriptional programs. The lack of a comprehensive, transcriptome-based classification tool has hampered the use of subtype-specific insights in both research and clinical settings. Here, we present a machine learning-based classifier trained on transcriptomic data to predict previously defined multi-omic subtypes of T-cell acute lymphoblastic leukemia. The model accurately assigns subtype identity across patient samples and cell lines, and provides a practical tool for standardized molecular stratification, supporting future integration into diagnostic and translational workflows, as demonstrated by its ability to reveal subtype-specific patterns of relapse.

bioinformatics↗

bioRxiv2023

The Sin3B chromatin modifier restricts cell cycle progression to dictate hematopoietic stem cell differentiation

Abstract/SummaryTo maintain blood homeostasis, millions of terminally differentiated effector cells are produced every day. At the apex of this massive and constant blood production lie hematopoietic stem cells (HSCs), a rare cell type harboring unique self-renewal and multipotent properties. A key feature of HSCs is their ability to temporarily exit the cell cycle in a state termed quiescence. Defective control of cell cycle progression can eventually lead to bone marrow failure or malignant transformation. It is thought that HSCs must re-enter the cell cycle in order to commit to terminal differentiation. However, the molecular mechanisms tying cell cycle re-entry to cell fate commitment in HSCs remain elusive. Here, we identify the chromatin-associated Sin3B protein as a molecular link between cell cycle progression and differentiation in HSCs. We demonstrate that Sin3B is necessary for HSCs commitment to differentiation, but dispensable for their self-renewal or survival. Single cell transcriptional profiling of hematopoietic stem and progenitor cells (HSPCs) inactivated for Sin3B reveals aberrant cell cycle gene expression, consistent with the observed aberrant progression through the G1 phase of the cell cycle. The defective cell cycle control elicited upon Sin3B inactivation correlates with the engagement of discrete signaling programs, including aberrant expression of cell adhesion molecules and essential components of the interferon signaling cascade in LT-HSCs. Additionally, chromatin accessibility profiling in LT-HSCs reveals the Sin3B-dependent accessibility of genomic elements controlling HSC differentiation, suggesting a functional link between cell cycle progression, and priming of hematopoietic stem cells for differentiation. Together, these results point to controlled progression through the G1 phase of the cell cycle as a likely regulator of HSC lineage commitment through the modulation of chromatin features.

cell biology↗

bioRxiv2022

Germline Transmission of a Circular Human Artificial Chromosome in the Mouse

Although the structure and function of the alphoid-tetO Human Artificial Chromosome (tetO-HAC) has been previously described in cell culture models and somatically in the mouse, in vivo persistence and stability throughout meiosis and across generations were not evaluated. Here we report germline transmission of a circular tetO-HAC across three mouse generations without observable health or reproductive deficiencies. Furthermore, we show that the tetO-HAC is maintained without selection as an episome and can be efficiently transmitted by both ova and sperm.

synthetic biology↗

bioRxiv2022

Cell type-specific prediction of 3D chromatin architecture

The mammalian genome is spatially organized in the nucleus to enable cell type-specific gene expression. Investigating how chromatin organization determines this specificity remains a challenge. Methods for measuring the 3D chromatin organization, such as Hi-C, are costly and bear strong technical limitations, restricting their broad application particularly in high-throughput genetic perturbations. In this study, we present C.Origami, a deep neural network model that performs de novo prediction of cell type-specific chromatin organization. The C.Origami model enables in silico experiments to examine the impact of genetic perturbations on chromatin interactions in cancer genomes and beyond. In addition, we propose an in silico genetic screening framework that enables high-throughput identification of impactful genomic regions on 3D chromatin organization. We demonstrate that cell type-specific in silico genetic perturbation and screening, enabled by C.Origami, can be used to systematically discover novel chromatin regulatory mechanisms in both normal and disease-related biological systems.

genomics↗

bioRxiv2019

Dynamic 3D chromosomal landscapes in acute leukemia

Three-dimensional (3D) chromatin architectural changes can alter the integrity of topologically associated domains (TADs) and rewire specific enhancer-promoter interactions impacting gene expression. Recently, such alterations have been implicated in human disease, highlighting the need for a deeper understanding of their role. Here, we investigate the reorganization of chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) using primary human leukemia specimens and its dynamic responses to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-Seq and CTCF ChIP-Seq datasets revealed widespread changes in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD \"fusion\" event being associated with loss of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data show that small molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation reduce specific 3D interactions associated with transformation. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.\n\nOne Sentence Summary3D chromatin alterations in T cell leukemia are accompanied by changes in insulation and oncogene expression and can be partially restored by targeted drug treatments.

cancer biology↗