Biology subjects

Matthess, Y.

Publications and source records attributed to Matthess, Y..

3 recordsLinked to original sources

bioRxiv2026

Genome-scale mapping of variant, enhancer and gene function in primary human CD4+ T cells

CD4+ T cells harbor a disproportionate enrichment of immune disease risk loci and represent the primary cellular context for immune disease biology, yet the genes and regulatory programs these variants affect remain largely unknown. We combined targeted Perturb-seq of 1,032 cis-regulatory elements (CREs) overlapping 4,724 variants across 14 immune diseases with genome-wide Perturb-seq of all expressed genes in primary human CD4+ T cells, spanning 4.1 million cells. We identified 626 CRE-gene pairs, and connected CRE targets to downstream regulatory cascades. At the TYK2 and DEXI/CLEC16A loci, we resolved target genes and linked noncoding variants to inflammatory and metabolic programs. Across diseases, we revealed that dispersed variants converged on shared and disease-specific programs. Our work provides a framework for tracing variant-to-CRE-to-gene-to-network in disease-relevant primary cells.

genetics↗

bioRxiv2025

Ferroptosis governs lymphatic vessel growth and regression

Whether, when, and how lymphatic vessels undergo cell death remains poorly understood. Here we identify ferroptosis as a physiological, cell-intrinsic regulator of the lymphatic endothelial cell survival during development and following injury, in stark contrast to the resilient organotypic blood endothelial cells. The lymphatic susceptibility to ferroptosis stems from tampered cystine/ hydropersulfide metabolism, alongside reduced glutathione availability triggered by an SH3RF3 E3 ligase mediated GPX4 degradation, and enhanced integration of polyunsaturated fatty acid enriched membrane phospholipids. Inducing ferroptosis genetically or pharmacologically elevated lymphatic lipid peroxidation, halted embryonic lymphangiogenesis and prevented post-injury lymphatic overgrowth while simultaneously shaped immune responses. Conversely, ferroptosis inhibition through saturated fatty acid supplementation led to pathological lymphatic hyperplasia. Targeting lymphatic ferroptotic mechanisms holds promise against pathological lymphatic growth in response to injury.

cell biology↗

bioRxiv2025

Differentiation hierarchy in adult B cell acute lymphoblastic leukemia at clonal resolution

While a differentiation hierarchy with leukemia-initiating stem cells (LICs) at the apex is well documented for acute myeloid leukemia, the existence of LICs and their trajectories in B cell acute lymphoblastic leukemia (B-ALL) are debated. B-ALL is a malignant disease displaying considerable phenotypical and functional heterogeneity, yet the underlying cellular organization remains largely elusive. This study aims to investigate the hierarchical landscape of B-ALL by combining barcoding and multiome single cell data to unveil the differentiation architecture and temporal dynamics of leukemic differentiation at clonal and single cell resolution in vivo. Single-cell transcriptome and AbSeq analysis of lentiviral barcoded and transplanted patient-derived B-ALL cells revealed interconnected subpopulations, which could be prospectively isolated via surface markers and exhibited distinct leukemogenicity. Barcode tracking demonstrated the ability of cells to differentiate from a source cluster into differentiated progeny. Using machine learning we identified expression patterns predicting their differentiation potential of each barcoded cell within the immature cell compartment. To determine the dynamical properties of clones, we have designed a mathematical model that simulates the development of these subpopulations from a clonally diverse stem cell compartment. The model confirmed the most likely cluster of origin, supporting our functional data, and revealed the variability in dynamical properties between clones, while largely excluding plasticity. Hence, our work demonstrates a unidirectional differentiation in B-ALL with an immature population exhibiting a high leukemogenic potential. Key pointsO_LIA differentiation hierarchy with distinct leukemogenesis potential in B-ALL is demonstrated via clonal tracing and mathematical modeling. C_LIO_LIClonal differentiation behavior, while heterogeneous, is cell intrinsically controlled and predictable, yet independent from expansion. C_LI

cancer biology↗