Biology subjects

Venters, B. J.

Publications and source records attributed to Venters, B. J..

6 recordsLinked to original sources

bioRxiv2026

Spatially-resolved single cell atlas of liposarcoma reveals lineage hierarchies, immune niches, and regulatory circuits

Well-differentiated and dedifferentiated liposarcoma (WDLPS and DDLPS) exhibit markedly different clinical behaviors, with DDLPS showing greater aggressiveness, higher recurrence and metastasis rates, and worse outcomes. Using single-nucleus multiome sequencing, epigenomic profiling, and spatial transcriptomics, we characterized cellular and epigenetic heterogeneity between these subtypes at single-cell and spatial resolution. We found distinct phenotypic states reflecting altered lineage differentiation and plasticity: DDLPS is dominated by early-differentiated progenitor-like cells, sclerotic WDLPS displays broader mesenchymal lineage plasticity, and adipocytic WDLPS contains abundant committed adipocytes. The DDLPS immune microenvironment was dominated by immunosuppressive macrophages, whereas WDLPS harbored more T cells and inflammatory macrophages. Notably, sclerotic WDLPS displayed intermediate cellular and molecular features, suggesting it may represent a distinct WDLPS subtype. Importantly, we identified novel gene regulatory circuits underlying each state, including FABP4/PPARG programs in adipocytic WDLPS, GLI2/TCF7L2/RBPJ/KLF7 programs in sclerotic WDLPS, and KLF7/FOSL2/SP3/GLI2/RBPJ programs in DDLPS. H3K27ac-marked enhancers were enriched near adipocytic marker genes in WDLPS and mesenchymal markers in DDLPS. Together, these findings reveal the cellular heterogeneity of tumor and immune compartments across liposarcoma subtypes and identify regulatory programs driving their differentiation states. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/713651v1_ufig1.gif" ALT="Figure 1"> View larger version (73K): org.highwire.dtl.DTLVardef@1c84ee1org.highwire.dtl.DTLVardef@1b2ad42org.highwire.dtl.DTLVardef@18ce5a6org.highwire.dtl.DTLVardef@138f615_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Nucleosome context regulates chromatin reader preference

Chromatin is more than a simple genome packaging system, and instead locally distinguished by histone post-translational modifications (PTMs) that can directly change nucleosome structure and / or be "read" by chromatin-associated proteins to mediate downstream events. An accurate understanding of histone PTM binding preference is vital to explain normal function and pathogenesis, and has revealed multiple therapeutic opportunities. Such studies most often use histone peptides, even though these cannot represent the full regulatory potential of nucleosome context. Here we apply a range of complementary and easily adoptable biochemical and genomic approaches to interrogate fully defined peptide and nucleosome targets with a diversity of mono or multivalent chromatin readers. In the resulting data, nucleosome context consistently refined reader binding, and multivalent engagement was more often regulatory than simply additive. This included abrogating the binding of the Polycomb group L3MBTL1 MBT to histone tails with lower methyl states (me1 or me2 at H3K4, H3K9, H3K27, H3K36 or H4K20); and confirmation that the CBX7 chromodomain and AT-hook-like motif (CD-ATL) tandem act as a functional unit to confer specificity for H3K27me3. Further, in vitro nucleosome preferences were confirmed by in vivo reader-CUT&RUN genomic mapping. Such data confirms that more representative chromatin substrates provide greater insight to biological mechanism and its disorder in human disease.

biochemistry↗

bioRxiv2024

High-efficiency genomic mapping of chromatin-associated targets with CUT&RUN

The precise regulation of chromatin composition is critical to gene expression and cellular identity, and thus a key component in development and disease. Robust assays to study chromatin features, including histone post-translational modifications (PTMs) and chromatin-associated proteins (e.g., transcription factors or PTM readers), are essential to understand their function and identify novel therapeutic strategies. To this end, Cleavage Under Targets and Release Using Nuclease (CUT&RUN) has emerged as a powerful tool for high-resolution epigenomic profiling. The approach has been successfully applied to numerous cell and tissue types, informing on target genomic distribution with unprecedented sensitivity and throughput. Here, we provide a detailed CUT&RUN protocol from sample collection through data analysis, including best practices and defined controls to ensure specific, efficient, and robust target profiling.

genomics↗

bioRxiv2024

Cancer-associated DNA Hypermethylation of Polycomb Targets Requires DNMT3A Dual Recognition of Histone H2AK119 Ubiquitination and the Nucleosome Acidic Patch

During tumor development, promoter CpG islands (CGIs) that are normally silenced by Polycomb repressive complexes (PRCs) become DNA hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) catalyze CpG methylation at PRC-regulated regions remains unclear. Here we report a cryo-EM structure of the DNMT3A long isoform (DNMT3A1) N-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine 119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 N-terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Furthermore, aberrant redistribution of DNMT3A1 to Polycomb target genes inhibits their transcriptional activation during cell differentiation and recapitulates the cancer-associated DNA hypermethylation signature. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for countering promoter CGI DNA hypermethylation, a major molecular hallmark of cancer.

cancer biology↗

bioRxiv2022

Nucleosome conformation dictates the histone code

Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized codes that are read by specialized regions (reader domains) in chromatin associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP-histone PTM] specificity, and thus decipher the histone code / guide epigenetic therapies. However, this has largely been done using a reductive approach of isolated reader domains and histone peptides, with the assumption that PTM readout is unaffected by any higher order factors. Here we show that CAP-histone PTM interaction is in fact dependent on nucleosome context. Our results indicate this is due to histone tail accessibility and the associated impact on binding potential of reader domains. We further demonstrate that the in vitro specificity of a tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. This necessitates we refine the histone code concept and interrogate it at the nucleosome level.

genomics↗

bioRxiv2020

Erythropoietin regulates transcription and YY1 dynamics in a pre-established chromatin architecture

The three dimensional architecture of the genome plays an essential role in establishing and maintaining cell identity. By contrast, the magnitude and temporal kinetics of changes in chromatin structure that arise during cell differentiation remain poorly understood. Here, we leverage a murine model of erythropoiesis to study the relationship between chromatin conformation, the epigenome, and transcription in erythroid cells. We discover that acute transcriptional responses induced by erythropoietin (EPO), the hormone necessary for erythroid differentiation, occur within an invariant chromatin topology. Within this pre-established landscape, Yin Yang 1 (YY1) occupancy dynamically redistributes to sites in proximity to EPO-regulated genes. Using HiChIP, we identify chromatin contacts mediated by H3K27ac and YY1 that are enriched for enhancer-promoter interactions of EPO-responsive genes. Taken together, these data are consistent with an emerging model that rapid, signal-dependent transcription occurs in the context of a pre-established chromatin architecture.

molecular biology↗