Biology subjects

Saintilnord, W. N.

Publications and source records attributed to Saintilnord, W. N..

4 recordsLinked to original sources

bioRxiv2025

Integrated Proteomic and Epigenomic Analysis Reveals IGF2 as a Vulnerability in PRC2-Deficient Malignant Peripheral Nerve Sheath Tumors

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with limited therapeutic options. Loss of the Polycomb repressive complex 2 (PRC2), via inactivating mutations in SUZ12 or EED, occurs frequently in MPNSTs and is associated with poor prognosis. However, the downstream chromatin and signaling consequences of these mutations remain incompletely understood. Here, we show that PRC2 deficiency in MPNST cells induces coordinated chromatin remodeling, characterized by loss of repressive H3K27me3 and gain of activating marks, including H3K27ac and H3K36me2. Integrative epigenomic, transcriptomic, and proteomic profiling revealed that this chromatin reprogramming activates a fetal-like growth signature centered on insulin-like growth factor 2 (IGF2) and its post-transcriptional regulators, Insulin-like Growth Factor 2 mRNA-Binding Protein (IGF2BP1-3). Functional studies demonstrate that PRC2-deficient cells are selectively dependent on IGF2 for proliferation, and that restoration of SUZ12 suppresses IGF2 expression and reduces growth. Analysis of human MPNST tumors confirms upregulation of the IGF2-IGF2BP axis in PRC2-deficient tumors, highlighting its clinical relevance. Together, these findings link PRC2 loss to activation of fetal growth factor-driven oncogenic signaling and identify IGF2 and its regulatory network as potential vulnerabilities in this aggressive tumor subtype.

cancer biology↗

bioRxiv2024

Incorporating histone H2B variants into chromatin modifies chromatin accessibility to induce epithelial to mesenchymal transition in breast cancer

Histones scaffold genomic DNA and regulate access to the transcriptional machinery. However, naturally occurring histone variants can alter histone-DNA interactions, DNA and histone modifications, and the chromatin interactome. Hence, alterations in histone variant deposition can disrupt chromatin, and are increasingly recognized as a way to trigger various disease, including cancer. While significant attention has been placed on the biochemical and functional roles of H2A, H3, and H4 histone variants, the variants of H2B remain largely understudied. Here, we show that H2B variants are dysregulated in breast cancer and that certain variants are associated with specific breast cancer subtypes. HIST1H2BO overexpression (in particular) is more common in Asian, African American/Black, and young female populations and is associated with a worse prognosis. In vitro studies show that H2B1O compacts nucleosome structure. Incorporating H2B1O into chromatin activates pro-inflammatory and oncogenic pathways, induces the epithelial-to-mesenchymal transition (EMT), and generates resistance to first-line chemotherapeutic agents. Thus, H2B1O acts much like an onco-histone, with H2B variant expression being a prognostic biomarker for breast cancer and a potential new target for drug therapies to enhance treatment efficacy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/627414v1_ufig1.gif" ALT="Figure 1"> View larger version (106K): org.highwire.dtl.DTLVardef@12c21dcorg.highwire.dtl.DTLVardef@631f3aorg.highwire.dtl.DTLVardef@1972244org.highwire.dtl.DTLVardef@14ab3b1_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Characterizing cytosine methylation of polymorphic human transposable element insertions using human pangenome resources

Cytosine methylation, a crucial epigenetic modification, plays a vital role in genomic regulation. Leveraging the advancements in third-generation sequencing, we investigated the methylation patterns of non-reference insertions of human lymphoblastoid cell lines (LCLs), particularly polymorphic transposable elements (TEs). We validated the high concordance between long-read methylation calls and conventional whole genome bisulfite sequencing (WGBS) method. By characterizing thousands of polymorphic TE insertions genome-wide using long reads from the draft Human Pangenome Reference, we aimed to establish general rules of TE methylation by addressing three key questions: 1) what is the methylation profile of each insertion? 2) do newly inserted TEs adopt the methylation pattern of their genomic context? and 3) do new TE insertions affect the methylation of their flanking regions? While most non-TE insertions exhibit DNA methylation patterns consistent with their genomic context, TE insertions are generally highly methylated, exhibiting distinct, class-specific patterns, and with profound variation within TE bodies. A small percentage of Alu insertions are hypomethylated, particularly those inserted within hypomethylated CpG islands. By comparing DNA methylation of flanking regions of TE insertions between individuals with and without the TE insertions, we revealed that majority of TEs exhibited minimal impact on nearby regions, although numerous exceptions exist where the methylation status of both L1 and Alu insertions "leak" into nearby regions, leading to either methylation spreading or hypomethylation sloping shores. In conclusion, we demonstrated the methylation calling capability of third-generation sequencing and its unique advantage in characterizing epigenomic features within non-reference positions. While TE insertions primarily exhibit methylation patterns restricted within their boundaries, some TEs are able to engage in context-dependent complex interactions with genomic neighborhood.

bioinformatics↗

bioRxiv2024

Aberrant expression of histone H2B variants reshape chromatin and alter oncogenic gene expression programs

Chromatin architecture governs DNA accessibility and gene expression. Thus, any perturbations to chromatin can significantly alter gene expression programs and promote disease. Prior studies demonstrate that every amino acid in a histone is functionally significant, and that even a single amino acid substitution can drive specific cancers. We previously observed that naturally occurring H2B variants are dysregulated during the epithelial to mesenchymal transition (EMT) in bronchial epithelial cells. Naturally occurring H2B variants differ from canonical H2B by only a few amino acids, yet single amino acid changes in other histone variants (e.g., H3.3) can drive cancer. We therefore hypothesized that H2B variants might function like oncohistones, and investigated how they modify chromatin architecture, dynamics, and function. We find that H2B variants are frequently dysregulated in many cancers, and correlate with patient prognosis. Despite high sequence similarity, mutations in each H2B variant tend to occur at specific "hotspots" in cancer. Some H2B variants cause tighter DNA wrapping around nucleosomes, leading to more compact chromatin structures and reduced transcription factor accessibility to nucleosomal DNA. They also altered genome-wide accessibility to oncogenic regulatory elements and genes, with concomitant changes in oncogenic gene expression programs. Although we did not observe changes in cell proliferation or migration in vitro, our Gene Ontology (GO) analyses of ATAC-seq peaks and RNA-seq data indicated significant changes in oncogenic pathways. These findings suggest that H2B variants may influence early-stage, cancer-associated regulatory mechanisms, potentially setting the stage for oncogenesis later on. Thus, H2B variant expression could serve as an early cancer biomarker, and H2B variants might be novel therapeutic targets.

cancer biology↗