Biology subjects

Corveleyn, L.

Publications and source records attributed to Corveleyn, L..

7 recordsLinked to original sources

bioRxiv2026

NAD Metabolism Drives CTCF-Cohesin Chromatin Regulation in EBV-Transformed B-Cells

Chromatin architecture regulates gene expression, and it is maintained by architectural proteins such as CTCF and the cohesin complex. In Epstein Barr virus infected cells, viral chromatin organization is stabilized through the interaction between PARP1 and CTCF, ensuring maintenance of latent gene expression. EBV B cells exhibit elevated PARP1 activity, which imposes a substantial metabolic burden due to NAD consumption by PARP1 itself. We demonstrate that efficient EBV infection and B-cell transformation rely on the NAD salvage pathway to sustain PARP1 activity and CTCF and cohesin chromatin folding. Pharmacologic inhibition of the rate-limiting enzyme NAMPT with FK866 phenocopies the chromatin architectural disruption induced by PARP1 and changes in NAD levels affects CTCF/cohesin chromatin architectural remodeling and loop extrusion. Moreover, NAMPT inhibition reduces tumor burden in EBV xenograft models. These findings identify a critical metabolic dependency linking NAD homeostasis to CTCF-cohesin mediated chromatin architecture and reveal a therapeutic vulnerability in EBV-associated malignancies.

microbiology↗

bioRxiv2026

Focus on the edges: a biomolecular network of histone PTMs, metabolites and proteins unveils functional entanglement in AML

The cell phenotype is not a direct manifestation of the genotype but rather a product of cellular history and the environmental context. However, individual biomolecules cannot change independently and show coordinated behavior. To study this in acute myeloid leukemia (AML), we built a unique multi-omics biomolecular network made from proteins, metabolites and histone posttranslational modifications (hPTMs) sequentially extracted from each cell pellet. Edges between the nodes are measured directly using 400 LC-MSMS runs that cover 18 AML cell lines. We provide a novel conceptual framework to illustrate the different classes of functional entanglement between and within omics layers and present the data in three interactive data browsers to allow full community access. To help navigate the network, we approach it from the perspective of two biomolecular targets, i.e. CD34 and the epigenetic mark Histone H3 lysine 27 trimethylation (H3K27me3). Now, this easily accessible biomolecular network serves as a starting point for building and testing hypotheses and streamlining drug development, in the process positioning biomolecular associations center stage in understanding phenotypic complexity.

cancer biology↗

bioRxiv2025

Profiling histone post-translational modifications to identify signatures of epigenetic drug response in T-cell acute lymphoblastic leukemia

Epigenetic modifications are dynamic and reversible, making them attractive targets for therapeutic intervention in cancer. Although several epigenetic drugs (epidrugs) have been clinically approved, their application in T-cell acute lymphoblastic leukemia (T-ALL) remains limited, and predictive biomarkers of response are lacking. Here, we present a mass spectrometry (MS)-based pharmacoepigenetic approach to profile histone post-translational modifications (hPTMs) to identify signatures associated with epidrug sensitivity in T-ALL. Baseline hPTM landscapes were previously established by our group for 21 T-ALL cell lines using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Here, we treated these cell lines with a panel of nine epidrugs including anthracyclines, histone deacetylase inhibitors, and DNA methyltransferase inhibitors. Correlation of cell viability data with hPTM levels revealed distinct hPTM signatures linked to sensitivity for each drug class. These signatures were subsequently evaluated in T-ALL patient-derived xenograft (PDX) models. However, we our analysis revealed substantial discepancies in hPTM sensitivity signatures compared to those observed in vitro. Co-variation network analysis highlighted divergence in hPTM-hPTM correlation between the two models, underscoring limitations of cell lines for modeling dynamic epigenetic regulation in vivo. Our findings establish a framework for MS-based hPTM profiling in T-ALL and emphasize the importance of model selection in developing predictive epigenetic biomarkers. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/673463v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1b15092org.highwire.dtl.DTLVardef@20bed5org.highwire.dtl.DTLVardef@1d0a687org.highwire.dtl.DTLVardef@1652999_HPS_FORMAT_FIGEXP M_FIG C_FIG Global hPTM profiling of 21 T-ALL cell lines was performed using LC-MS/MS, as previously published by Provez et al. In parallel, the 21 cell lines were treated with a dilution series of nine epidrugs, categorized into three distinct classes, to determine their IC50 values. Finally, Spearman correlation analysis was performed to assess the relationship between hPTM levels and drug sensitivity. Figure created with Biorender.com.

cancer biology↗

bioRxiv2024

Two H3K23 histone methyltransferases, SET-32 and SET-21, function synergistically to promote nuclear RNAi-mediated transgenerational epigenetic inheritance in Caenorhabditis elegans

Nuclear RNAi in C. elegans induces a set of transgenerationally heritable marks of H3K9me3, H3K23me3, and H3K27me3 at the target genes. The function of H3K23me3 in the nuclear RNAi pathway is largely unknown due to the limited knowledge of H3K23 histone methyltransferase (HMT). In this study we identified SET-21 as a novel H3K23 HMT. By taking combined genetic, biochemical, imaging, and genomic approaches, we found that SET-21 functions synergistically with a previously reported H3K23 HMT SET-32 to deposit H3K23me3 at the native targets of germline nuclear RNAi. We identified a subset of native nuclear RNAi targets that are transcriptionally activated in the set-21;set-32 double mutant. SET-21 and SET-32 are also required for robust transgenerational gene silencing induced by exogenous dsRNA. The set-21;set-32 double mutant strain exhibits an enhanced temperature-sensitive mortal germline phenotype compared to the set-32 single mutant, while the set-21 single mutant animals are fertile. We also found that HRDE-1 and SET-32 are required for cosuppression, a transgene-induced gene silencing phenomenon, in C. elegans germline. Together, these results support a model in which H3K23 HMTs SET-21 and SET-32 function cooperatively to ensure the robustness of germline nuclear RNAi and promotes the germline immortality under the heat stress.

molecular biology↗

bioRxiv2024

Mass Spectrometry-based Profiling of Single-cell Histone Post-translational Modifications to Dissect Chromatin Heterogeneity

Single-cell proteomics confidently quantifies cellular heterogeneity, yet precise quantification of post-translational modifications, such as those deposited on histone proteins, has remained elusive. Here, we developed a robust mass spectrometry-based method for the unbiased analysis of single-cell histone post-translational modifications (schPTM). schPTM identifies both single and combinatorial histone post-translational modifications (68 peptidoforms in total), which includes nearly all frequently studied histone post-translational modifications with comparable reproducibility to traditional bulk experiments. As a proof of concept, we treated cells with sodium butyrate, a histone deacetylase inhibitor, and demonstrated that our method can i) distinguish between treated and non-treated cells, ii) identify sub-populations of cells with heterogeneous response to the treatment, and iii) reveal differential co-regulation of histone post-translational modifications in the context of drug treatment. The schPTM method enables comprehensive investigation of chromatin heterogeneity at single-cell resolution and provides further understanding of the histone code.

molecular biology↗

bioRxiv2022

An interactive mass spectrometry atlas of histone posttranslational modifications in T-cell acute leukemia

The holistic nature of omics studies makes them ideally suited to generate hypotheses on health and disease. Sequencing-based genomics and mass spectrometry (MS)-based proteomics are linked through epigenetic regulation mechanisms. However, epigenomics is currently mainly focused on DNA methylation status using sequencing technologies, while studying histone posttranslational modifications (hPTMs) using MS is lagging, partly because reuse of raw data is impractical. Yet, targeting hPTMs using epidrugs is an established promising research avenue in cancer treatment. Therefore, we here present the most comprehensive MS-based preprocessed hPTM atlas to date, including 21 T-cell acute lymphoblastic leukemia (T-ALL) cell lines. We present the data in an intuitive and browsable single licensed Progenesis QIP project and provide all essential quality metrics, allowing users to assess the quality of the data, edit individual peptides, try novel annotation algorithms and export both peptide and protein data for downstream analyses, exemplified by the PeptidoformViz tool. This data resource sets the stage for generalizing MS-based histone analysis and provides the first reusable histone dataset for epidrug development.

cancer biology↗

bioRxiv2021

Histone sample preparation for bottom-up mass spectrometry: a roadmap to informed decisions

Histone-based chromatin organization enabled eukaryotic genome complexity. This epigenetic control mechanism allowed for the differentiation of stable gene-expression and thus the very existence of multicellular organisms. This existential role in biology makes histones one of the most complexly modified molecules in the biotic world, which makes these key regulators notoriously hard to analyze. We here provide a roadmap to enable fast and informed selection of a bottom-up mass spectrometry sample preparation protocol that matches a specific research question. We therefore propose a two-step assessment procedure: (i) visualization of the coverage that is attained for a given workflow and (ii) direct alignment-between-runs to assess potential pitfalls at the ion level. To illustrate the applicability, we compare four different sample preparation protocols, while adding a new enzyme to the toolbox, i.e., RgpB (GingisREX(R), Genovis), an endoproteinase that selectively and efficiently cleaves at the c-terminal end of arginine residues. Raw data is available via ProteomeXchange with identifier PXD024423.

molecular biology↗