Biology subjects

Meissner, B.

Publications and source records attributed to Meissner, B..

5 recordsLinked to original sources

bioRxiv2026

Developmental origins of thymic B-cell lymphomas

The thymus provides a specialized niche for lymphocyte differentiation, yet the developmental trajectories of its rare B-cell population and their relationship to thymic B-cell lymphomagenesis remain poorly understood. Here, we integrate single-cell multiomics and spatial profiling across human tissues to delineate a B-cell differentiation program selectively represented in the human thymus. This program links CCL17 and germinal center-like B-cell states along a trajectory distinct from canonical germinal center differentiation and can be recapitulated in vitro by signals operating in the thymic medulla. Extending this framework across human B-cell lymphomas, we identify an inherent malignant cell state in PMBCL that shares transcriptional and epigenetic features with CCL17 thymic B cells. This malignant state associates with early clonal positions in reconstructed B-cell receptor phylogenies and persists within tumor microenvironments distinct from the thymic niche. Together, these findings support a model in which thymus-specific B-cell differentiation programs are redeployed during thymic B-cell lymphomagenesis.

cancer biology↗

bioRxiv2026

Multi-omic long-read sequencing reveals nucleosome control of transcriptional fidelity at the isoform level

Transcription and RNA processing are tightly coupled to chromatin organization, yet how nucleosome positioning is coordinated across the promoter and gene body to shape alternative isoform expression remains poorly understood. This question has been difficult to address because short-read chromatin profiling cannot simultaneously capture promoter and gene-body chromatin states on the same DNA molecule, and short-read RNA sequencing cannot resolve full-length transcripts without requiring computational assembly. To address this, we deleted two conserved chromatin remodelers, ISW1 and CHD1, in Saccharomyces cerevisiae and profiled chromatin fibers, nascent RNA, and full-length mature RNA using Oxford Nanopore long-read sequencing. We developed EpiFLAIR, a computational framework that assigns discrete long-range chromatin states across entire genes and integrates these states with isoform-level transcriptional outputs. Using EpiFLAIR, we show that single-molecule chromatin states together with sequence motifs are strong predictors of alternative TSS isoform expression. Loss of ISW1 and CHD1 produced divergent transcriptional changes by activating transcriptionally silenced promoters while repressing active ones. Single-molecule chromatin profiling suggested that this redistribution of transcriptional activity arose, in part, from an anticorrelation between gene-body and promoter chromatin accessibility along the same chromatin fiber, a finding uniquely enabled by long-read single-molecule resolution. Furthermore, disruption of regular nucleosome spacing impaired RNAPII processivity and co-transcriptional splicing, consequently altering mature RNA levels and splicing isoform composition. Together, our findings demonstrate that nucleosomes maintain transcriptional fidelity during initiation, elongation, and splicing to regulate isoform expression. More broadly, long-read single-molecule chromatin profiling represents a powerful approach for linking chromatin organization to isoform-level gene regulation.

genomics↗

bioRxiv2024

Probing chromatin accessibility with small molecule DNA intercalation and nanopore sequencing

Studies of in vivo chromatin organization have relied on the accessibility of the underlying DNA to nucleases or methyltransferases, which is limited by their requirement for purified nuclei and enzymatic treatment. Here, we introduce a nanopore-based sequencing technique called Small-Molecule Adduct sequencing (SMAdd-seq), where we profile chromatin accessibility by treating nuclei or intact cells with a small molecule, angelicin. Angelicin reacts with thymine bases in linker DNA not bound to core nucleosomes after UV light exposure, thereby labeling accessible DNA regions. By applying SMAdd-seq in Saccharomyces cerevisiae, we demonstrate that angelicin-modified DNA can be detected by its distinct nanopore current signals. To systematically identify angelicin modifications and analyze chromatin structure, we developed a neural network model, NEural network for mapping MOdifications in nanopore long-reads (NEMO). NEMO accurately called expected nucleosome occupancy patterns near transcription start sites at both bulk and single-molecule levels. We observe heterogeneity in chromatin structure and identify clusters of single-molecule reads with varying configurations at specific yeast loci. Furthermore, SMAdd-seq performs equivalently on purified yeast nuclei and intact cells, indicating the promise of this method for in vivo chromatin labeling on long single molecules to measure native chromatin dynamics and heterogeneity. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/585815v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@14a0f8dorg.highwire.dtl.DTLVardef@143030eorg.highwire.dtl.DTLVardef@7d8ed4org.highwire.dtl.DTLVardef@12c3b05_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2019

Coding and regulatory drivers of mantle cell lymphoma identified through exome and genome sequencing

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features known to contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes alongside previously published exome cohorts. To confirm our findings, we re-sequenced the genes identified in the exome cohort in 212 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations and further nominate two additional genes, EWSR1 and MEF2B, whose mutation respectively associated with poor and good outcome. Our sequencing revealed novel recurrent mutations including a unique missense hot spot in MEF2B and a pattern of non-coding mutations surrounding a single exon of the HNRNPH1 gene. We sequenced the whole genomes of 34 MCLs to confirm the focal nature of HNRNPH1 mutations. Using RNA-seq data from 110 of these cases, we identified a functional role for recurrent non-coding HNRNPH1 mutations in disrupting an auto-regulatory feedback mechanism. Overall, we identified three novel MCL-related genes with roles in RNA trafficking or splicing, namely DAZAP1, EWSR1, and HNRNPH1. Taken together, these data strongly implicate a role for aberrant regulation of splicing in MCL pathobiology.\n\nKey pointsO_LIRNA-binding proteins with roles in regulating alternative splicing, DAZAP1, EWSR1, HNRNPH1, are frequently mutated in MCL\nC_LIO_LIThe majority of recurrent somatic HNRNPH1 mutations are intronic and HNRNPH1 exhibits self-regulation through alternative splicing\nC_LI

genomics↗

bioRxiv2017

Genome-wide discovery of somatic coding and regulatory variants in Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Many known driver mutations are over-represented in one of its two molecular subgroups, knowledge of which has aided in the development of therapeutics that target these features. The heterogeneity of DLBCL determined through prior genomic analysis suggests an incomplete understanding of its molecular aetiology, with a limited diversity of genetic events having thus far been attributed to the activated B-cell (ABC) subgroup. Through an integrative genomic analysis we uncovered genes and non-coding loci that are commonly mutated in DLBCL including putative regulatory sequences. We implicate recurrent mutations in the 3UTR of NFKBIZ as a novel mechanism of oncogene deregulation and found small amplifications associated with over-expression of FC-{gamma} receptor genes. These results inform on mechanisms of NF-{kappa}B pathway activation in ABC DLBCL and may reveal a high-risk population of patients that might not benefit from standard therapeutics.

genomics↗