Biology subjects

Zeitler, L.

Publications and source records attributed to Zeitler, L..

7 recordsLinked to original sources

bioRxiv2025

IL4i1-sourced oncometabolites promote neuroblastoma cell survival

High-risk neuroblastoma (NB) is driven by the amplification of MYCN in conjunction with additional oncogenic mutations in kinases such as ALK. NB cells require antioxidant responses to maintain redox balance and are highly sensitive to ferroptosis. Here, we show that metabolites derived from infiltrating immune cells expressing IL4i1, a secreted oxidoreductase, are potent suppressors of NB ferroptosis. IL4i1 metabolites (indole-3-pyruvate and 4-hydroxyphenylpyruvate) blocked ferroptosis in all human NB cell lines via a mechanism that depended on free radical scavenging and NRF2 activation but did not require the aryl hydrocarbon receptor. Supernatant transfer experiments confirmed that IL4i1 creates a milieu that protects NB cells from oxidative cell death. Importantly, mice lacking IL4i1 were protected from NB in a high-penetrance MYCN and mutant ALK-driven autochthonous cancer model. Therefore, we propose that immune IL4i1 is permissive for NB growth and survival. IL4i1 produces context-dependent oncometabolites and, as a secreted enzyme, represents a target for cell death manipulation in cancers sensitive to oxidative stress-driven cell death. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/669062v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@6e79baorg.highwire.dtl.DTLVardef@f9a9bcorg.highwire.dtl.DTLVardef@f6b2aaorg.highwire.dtl.DTLVardef@4bb764_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Alignment-free integration of single-nucleus ATAC-seq across species with sPYce

Changes in gene regulation largely contribute to differences in cellular identities and phenotypes between species. Single-nucleus assays for transposase-accessible chromatin with sequencing (snATAC-seq) are an efficient strategy to identify putative gene regulatory elements active in a given tissue at single-cell resolution, and have unprecedented potential to provide new insight into evolutionary divergence of regulatory programs. However, no dedicated framework exists to integrate and compare snATAC-seq data across species, whilst methods designed for single-cell gene expression data have serious limitations. Here, we present sPYce, a cross-species snATAC-seq integration method that relies on sequence composition similarities through k-mer histograms. In contrast to other approaches, sPYce does not require orthologous genes or genome alignments to anchor data from different species. Instead, it uses similarity in non-coding regulatory sequence motifs to uncover conserved cellular identities. sPYce can embed datasets from multiple species into the same mathematical space and permits further downstream analysis steps, such as dimensionality reduction, visualisation, clustering, cell type annotation transfer, and motif enrichment. We benchmarked sPYce against existing approaches on two publicly available datasets spanning more than 160 million years of evolution, demonstrating that it successfully uncovers conserved cellular programs whilst preserving biologically relevant species-specific differences. sPYce also implements a significance test for divergence of regulatory motifs between species. By comparing cerebellar development in mouse and opossum, we discovered regulatory divergence in granule cell differentiation programs, particularly driven by Nuclear Factor 1 (NF1). Our extensive evaluation suggests that sPYce is the first easy-to-use, alignment-free cross-species snATAC-seq integration approach, opening novel perspectives to compare gene regulatory evolution across species.

bioinformatics↗

bioRxiv2024

Using runs of homozygosity and machine learning to disentangle sources of inbreeding and infer self-fertilization rates

Runs of homozygosity (ROHs) are indicative of elevated homozygosity and inbreeding due to mating of closely related individuals. Self-fertilization can be a major source of inbreeding which elevates genomewide homozygosity and thus should also create long ROHs. While ROHs are frequently used to understand inbreeding in the context of conservation and selective breeding, as well as for consanguinity of populations and their demographic history, it remains unclear how ROH characteristics are altered by selfing and if this confounds expected signatures of inbreeding due to demographic change. Using simulations, we study the impact of the mode of reproduction and demographic history on ROHs. We apply random forests to identify unique characteristics of ROHs, indicative of different sources of inbreeding. We pinpoint distinct features of ROHs that can be used to better characterize the type of inbreeding the population was subjected to and to predict outcrossing rates and complex demographic histories. Using additional simulations and four empirical datasets, two from highly selfing species and two from mixedmaters, we predict the selfing rate and validate our estimations. We find that self-fertilization rates are successfully identified even with complex demography. Population genetic summary statistics improve algorithm accuracy particularly in the presence of additional inbreeding, e.g., from population bottlenecks. Our findings highlight the importance of ROHs in disentangling confounding factors related to various sources of inbreeding and demonstrate situations where such sources cannot be differentiated. Additionally, our random forest models provide a novel tool to the community for inferring selfing rates using genomic data.

genetics↗

bioRxiv2023

A Genome-Wide Comprehensive Analysis of Nucleosome Positioning in Yeast

In eukaryotic cells, the one-dimensional DNA molecules need to be tightly packaged into the spatially constraining nucleus. Folding is achieved on its lowest level by wrapping the DNA around nucleosomes. Their positioning regulates other nuclear processes, such as transcription and DNA repair. Despite strong efforts to study nucleosome phasing using Next Generation Sequencing (NGS) data, the mechanism of their collective arrangement along the gene body remains poorly understood. Here, we assess the nucleosome profiles of protein-coding genes in Saccharomyces cerevisiae using functional Principal Component Analysis. By decomposing the NGS signals into their main descriptive functions, we compared wild type and chromatin remodeler-deficient strains, keeping position-specific details preserved. A correlation analysis with other genomic properties, such as gene size and length of the upstream Nucleosome Depleted Region (NDR), identified key factors that influence nucleosome phasing. We reveal that the RSC chromatin remodeler--which is responsible for NDR maintenance--is indispensable for decoupling nucleosome arrangement within the gene from phasing outside, which interfere in rsc8-depleted conditions. Moreover, positioning in chd1{Delta} strains displayed a clear correlation with RNA polymerase II presence, whereas wild type cells did not indicate a noticeable interdependence. We propose that RSC is pivotal for global nucleosome organisation, whilst Chd1 plays a key role for maintaining local arrangement.

bioinformatics↗

bioRxiv2022

Functional interplay between Mediator and RSC chromatin remodeling complex controls nucleosome-depleted region maintenance at promoters

Chromatin organization is crucial for the transcriptional regulation in eukaryotes. Mediator is an essential and conserved coactivator thought to act in concert with chromatin regulators. However, it remains largely unknown how their functions are coordinated. Here, we provide evidence in the yeast Saccharomyces cerevisiae that Mediator establishes physical contact with RSC (Remodels the Structure of Chromatin), a conserved and essential chromatin remodeling complex that is crucial for nucleosome-depleted region (NDR) formation. We determined the role of Mediator-RSC interaction in their recruitment, nucleosome occupancy and transcription on a genomic scale. Mediator and RSC co-localize on wide NDRs of promoter regions, and specific Mediator mutations affect nucleosome eviction and TSS-associated +1 nucleosome stability. This work shows that Mediator contributes to RSC remodeling function to shape NDRs and maintain chromatin organization on promoter regions. It will help in our understanding of transcriptional regulation in the chromatin context relevant for severe diseases.

genomics↗

bioRxiv2021

Neuroblastoma formation requires unconventional CD4 T cells and myeloid amino acid metabolism

By mirroring their function as tissue repair organizers in normal tissues, immune cells regulate tumor growth. To understand the different facets of immune-tumor collaboration through genetics, spatial transcriptomics, and immunological manipulation with non-invasive, longitudinal imaging, we generated a penetrant double oncogene-driven autochthonous model of neuroblastoma. Using spatial transcriptomic analysis, we co-localized CD4+ and myeloid populations within the tumor parenchyma, while CD8+ T cells and B cells were peripherally dispersed. Depletion of CD4+ T cells or CCR2+ macrophages, but not B cells, CD8+, or NK cells, prevented tumor formation. Tumor CD4+ T cells displayed unconventional phenotypes, were clonotypically diverse, and antigen-independent. Within the myeloid fraction, tumor growth required myeloid cells expressing Arginase-1. Overall, our results suggest that arginine-metabolizing myeloid cells conspire with pathogenic CD4+ T cells to create permissive conditions for tumor formation, and therefore suggest that these pro-tumorigenic pathways can be disabled by targeting myeloid amino acid metabolism.

cancer biology↗

bioRxiv2019

Loss of diversity and accumulation of genetic load in doubled-haploid lines from European maize landrace

Maize landraces are well adapted to their local environments and present valuable sources of genetic diversity for breeding and conservation. But the maintenance of open-pollinated landraces in ex-situ programs is challenging, as regeneration of seed can often lead to inbreeding depression and the loss of diversity due to genetic drift. Recent reports suggest that the production of doubled-haploid (DH) lines from landraces may serve as a convenient means to preserve genetic diversity in a homozygous form that is immediately useful for modern breeding. The production of doubled-haploid (DH) lines presents an extreme case of inbreeding which results in instantaneous homozygosity genome-wide. Here, we analyzed the effect of DH production on genetic diversity, using genome-wide SNP data from hundreds of individuals of five European landraces and their related DH lines. In contrast to previous findings, we observe a dramatic loss of diversity at both the haplotype level and that of individual SNPs. We identify thousands of SNPs that exhibit allele frequency differences larger than expected under models of neutral genetic drift and document losses of shared haplotypes. We find evidence consistent with selection at functional sites that are potentially involved in the diversity differences between landrace and DH populations. Although we were unable to uncover more details about the mode of selection, we conclude that landrace DH lines may be a valuable tool for the introduction of variation into maize breeding programs but come at the cost of decreased genetic diversity and increased genetic load.

evolutionary biology↗