Biology subjects

Javierre, B. M.

Publications and source records attributed to Javierre, B. M..

8 recordsLinked to original sources

bioRxiv2025

Three-Dimensional Epigenome Roadmap of Human B-cell Differentiation Uncovers Mechanisms of Humoral Immunity and Oncogenesis

Human B-cell differentiation underlies humoral immunity, and its disruption leads to cancer, autoimmunity, and immunodeficiencies. However, the enhancer-based regulatory mechanisms governing this process remain poorly understood. To address this gap, we generated the first three-dimensional epigenomic roadmap of human B-cell differentiation in vivo. By profiling nine differentiation stages, we linked nearly half a million enhancers to their target genes through chromatin interactions, defined their activity states, and predicted bound transcription factors. We show that the acquisition of B-cell identity, distinct from common cellular processes, relies on large enhancer networks acting additively and synergistically to finely tune transcription. We further identify a 3D epigenetic priming mechanism underlying immune memory, whereby memory B cells retain primed DNA loops that enable faster responses to antigen re-exposure. Extending this roadmap to disease, we demonstrate that B-cell malignancies preserve enhancer signatures of their cell of origin while silencing distal tumor suppressor control. Finally, we uncover a previously unappreciated oncogenic mechanism in which intragenic deletions disrupt distal gene regulation via enhancer loss. Together, this resource provides a framework for understanding the genetic and epigenetic basis of humoral immunity and immune-related diseases.

genomics↗

bioRxiv2025

Decoding human B cell ontogeny in prenatal and adult bone marrow and in vitro models via single-cell multiomics

In humans, the bone marrow becomes the primary site for B lymphopoiesis during the second trimester of pregnancy and continues throughout life. Prenatal and adult B cell progenitors play distinct roles in the aetiology and pathology of paediatric and adult hematopoietic malignancies, though the molecular drivers of these differences remain unclear. Here, we created a comprehensive multiomics atlas of over 500k cells covering immune and stromal compartment from prenatal and adult bone marrow, enabling high-resolution analysis of the cell-intrinsic and cell-extrinsic processes that modulate prenatal and adult B lymphopoiesis. Even though B cells follow broadly similar developmental trajectories, we identify a novel postnatal lateCLP subset equivalent to prenatal preProB cells, and uncover prenatal cells carry several signatures characteristic of leukemias, including enhanced proliferation, higher RAG1/RAG2 activity, extrinsic B cell signals such as IL7, and lower retention signals in the bone marrow. We also developed and characterised, at both cellular and molecular levels, a new experimental framework for generating B cell precursors from human induced pluripotent stem cells (hiPSCs), and show that it faithfully recapitulates key stages of B cell differentiation. Together, our single-cell multiomics atlas of B lymphopoiesis in vivo and in vitro offers detailed insights into the unique molecular features of prenatal and adult B cell lymphopoiesis, and serves as a powerful resource for investigating the early events that contribute to haematological disorders.

immunology↗

bioRxiv2024

Age-Dependent Maturation and Rejuvenation of the Neural 3D Chromatin Interactome in Enriched Environments

Aging is a multifactorial biological process resulting in physiological and cellular decline. However, our understanding of age-related changes in 3D genome organization and the effect of external interventions on this process, remains limited. Here we describe alterations in the landscape of the 3D chromatin interactome upon aging, utilizing the low input Promoter Capture Hi-C (liCHi-C) technique with hippocampal neurons. We integrated liCHi-C data with RNA-seq data to identify functional implications. Furthermore, we assessed the effect of exposure to environmental enrichment (EE). Remarkably, our results demonstrated an age- dependent modulation of promoter interactions and expression with EE, with aging-like changes induced in young mice upon EE, likely associated with early brain maturation; while age-related alterations were reverted in old mice, leading to a partial rejuvenation of aged mouse hippocampi. These findings revealed a dynamic behaviour of the neuronal 3D chromatin structure over time, which can be modulated by external interventions.

genomics↗

bioRxiv2023

p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response

Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, using a multi-omics integration framework, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains and DNA loops within minutes of its activation, which escort the p53 transcriptional program along time. Focused on p53-bound enhancers, we report a core transcriptional program of 340 genes directly regulated by p53 over distance, most of these not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Taken together, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help future designs of p53-based cancer therapies.

genomics↗

bioRxiv2022

Low input capture Hi-C (liCHi-C) identifies promoter-enhancer interactions at high-resolution

Long-range interactions between regulatory elements and promoters are key in gene transcriptional control; however, their study requires large amounts of starting material, which is not compatible with clinical scenarios nor the study of rare cell populations. Here we introduce low input capture Hi-C (liCHi-C) as a cost-effective, flexible method to map and robustly compare promoter interactomes at high resolution. As proof of its broad applicability, we implement liCHi-C to study normal and malignant human hematopoietic hierarchy in clinical samples. We demonstrate that the dynamic promoter architecture identifies developmental trajectories and orchestrates transcriptional transitions during cell-state commitment. Moreover, liCHi-C enables the identification of new disease-relevant cell types, genes and pathways potentially deregulated by non-coding alterations at distal regulatory elements. Finally, we show that liCHi-C can be harnessed to uncover genome-wide structural variants, resolve their breakpoints and infer their pathogenic effects. Collectively, our optimized liCHi-C method expands the study of 3D chromatin organization to unique, low-abundance cell populations, and offers an opportunity to uncover novel factors and regulatory networks involved in disease pathogenesis.

genomics↗

bioRxiv2021

High-resolution simulations of chromatin folding at genomic rearrangements in malignant B-cells provide mechanistic insights on proto-oncogene deregulation

Genomic rearrangements are known to result in proto-oncogene deregulation in many cancers, but the link to genome 3D structure remains poorly understood. Here we used the highly-predictive heteromorphic polymer (HiP-HoP) model to predict chromatin conformations at the proto-oncogene CCND1 in healthy and malignant B-cells. After confirming that the model gives good predictions of Hi-C data for the non-malignant human B-cell derived cell line GM12878, we generated predictions for two cancer cell lines, U266 and Z-138. These possess genome rearrangements involving CCND1 and the immunoglobulin heavy chain locus (IGH), which we mapped using targeted genome sequencing. Our simulations showed that a rearrangement in U266 cells where a single IGH super-enhancer is inserted next to CCND1 leaves the local topologically associated domain (TAD) structure intact. We also observed extensive changes in enhancer-promoter interactions within the TAD, suggesting that it is the downstream chromatin remodelling which gives rise to the oncogene activation, rather than the presence of the inserted super-enhancer DNA sequence per se. Simulations of the IGH-CCND1 reciprocal translocation in Z-138 cells revealed that an oncogenic fusion TAD is created, encompassing CCND1 and the IGH super-enhancers. We predicted how the structure and expression of CCND1 changes in these different cell lines, validating this using qPCR and fluorescence in situ hybridization microscopy. Our work demonstrates the power of polymer simulations to predict differences in chromatin interactions and gene expression for different translocation break-points.

genomics↗

bioRxiv2019

Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility

Neutrophils play fundamental roles in innate inflammatory response, shape adaptive immunity1, and have been identified as a potentially causal cell type underpinning genetic associations with immune system traits and diseases2,3 The majority of these variants are non-coding and the underlying mechanisms are not fully understood. Here, we profiled the binding of one of the principal myeloid transcriptional regulators, PU.1, in primary neutrophils across nearly a hundred volunteers, and elucidate the coordinated genetic effects of PU.1 binding variation, local chromatin state, promoter-enhancer interactions and gene expression. We show that PU.1 binding and the associated chain of molecular changes underlie genetically-driven differences in cell count and autoimmune disease susceptibility. Our results advance interpretation for genetic loci associated with neutrophil biology and immune disease.

genetics↗

bioRxiv2018

Human pancreatic islet 3D chromatin architecture provides insights into the genetics of type 2 diabetes

Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer regions (enhancer clusters, stretch enhancers or super-enhancers). So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in 3D-space. Furthermore, their target genes are generally unknown. We have now created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers with their target genes, often located hundreds of kilobases away. It further revealed sets of islet enhancers, super-enhancers and active promoters that form 3D higher-order hubs, some of which show coordinated glucose-dependent activity. Hub genetic variants impact the heritability of insulin secretion, and help identify individuals in whom genetic variation of islet function is important for T2D. Human islet 3D chromatin architecture thus provides a framework for interpretation of T2D GWAS signals.

genomics↗