Biology subjects

Steiger, M.

Publications and source records attributed to Steiger, M..

5 recordsLinked to original sources

bioRxiv2026

Genome-wide multi-layered epigenomic profiling across human aging

Aging is characterized by highly reproducible alterations across multiple layers of the epigenetic landscape, including DNA methylation, chromatin accessibility, and histone modifications. However, it remains unclear to what extent these age-associated changes are interconnected and coordinated coherently. To investigate the genome-wide distribution and interplay of age-associated epigenetic alterations, we generated whole-genome bisulfite sequencing (WGBS) data from blood samples of 120 healthy donors. Integration with ATAC-seq data revealed no clear relationship between age-related changes in DNA methylation and chromatin accessibility. We further examined the association of these alterations with age-dependent changes in CTCF occupancy and histone modifications, including H3K27ac, H3K27me3, H3K4me1, H3K4me3, and H3K9me3, but observed very little corresponding changes in chromatin states. Collectively, our integrative genome-wide analysis revealed only limited association between age-associated epigenetic alterations in DNA methylation, chromatin accessibility, and histone modifications, arguing against a broadly coordinated remodeling of the aging epigenome.

genomics↗

bioRxiv2026

Multimodal single-cell analysis uncovers transcription factor networks underlying T-cell aging

Aging of the immune system is associated with chronic inflammation and impaired immune function, yet the regulatory mechanisms underlying these changes remain incompletely understood. Here, we generated paired single-cell transcriptomic and chromatin accessibility profiles from peripheral blood mononuclear cells of young and old healthy donors to characterize immune aging at single-cell resolution. Using an integrative computational framework for multi-omic single-cell analysis, we detected pronounced age-associated changes in T cells, including loss of naive CD8+ T cells and expansion of differentiated memory and effector populations. Aging was accompanied by increased inflammatory signaling and reduced oxidative phosphorylation programs. Enhancer-based gene regulatory network analyses identified a reduced role of TCF7 and increased activity of inflammatory regulators, including FOSL2, in aged T cells. Integration with genetic association and eQTL datasets further supported the functional relevance of age-associated regulatory regions and their target genes.

bioinformatics↗

bioRxiv2025

Human brain organoids record the passage of time over multiple years in culture

The human brain develops and matures over an exceptionally prolonged period of time that spans nearly two decades of life. Processes that govern species-specific aspects of human postnatal brain development are difficult to study in animal models. While human brain organoids offer a promising in vitro model, they have thus far been shown to largely mimic early stages of brain development. Here, we developed human brain organoids for an unprecedented 5 years in culture, optimizing growth conditions able to extend excitatory neuron viability beyond previously-known limits. Using module scores of maturation-associated genes derived from a time course of endogenous human brain maturation, we show that brain organoids transcriptionally age with cell type-specificity through these many years in culture. Whole-genome methylation profiling reveals that the predicted epigenomic age of organoids sampled between 3 months and 5 years correlates precisely with time spent in vitro, and parallels epigenomic aging in vivo. Notably, we show that in chimeric organoids generated by mixing neural progenitors derived from "old" organoids with progenitors from "young" organoids, old progenitors rapidly produce late neuronal fates, skipping the production of earlier neuronal progeny that are instead produced by their young counterparts in the same co-cultures. The data indicate that human brain organoids can mature and record the passage of time over many years in culture. Progenitors that age in organoids retain a memory of the time spent in culture reflected in their ability to execute age-appropriate, late developmental programs.

neuroscience↗

bioRxiv2021

Assessing genome-wide dynamic changes in enhancer activity during early mESC differentiation by FAIRE-STARR-seq

Embryonic stem cells (ESCs) can differentiate into any given cell type and therefore represent a versatile model to study the link between gene regulation and differentiation. To quantitatively assess the dynamics of enhancer activity during the early stages of murine ESC differentiation, we analyzed accessible genomic regions using STARR-seq, a massively parallel reporter assay. This resulted in a genome-wide quantitative map of active mESC enhancers, in pluripotency and during the early stages of differentiation. We find that only a minority of accessible regions is active and that such regions are enriched near promoters, characterized by specific chromatin marks, enriched for distinct sequence motifs, and modeling shows that active regions can be predicted from sequence alone. Regions that change their activity upon retinoic acid-induced differentiation are more prevalent at distal intergenic regions when compared to constitutively active enhancers. Further, analysis of differentially active enhancers verified the contribution of individual TF motifs toward activity and inducibility as well as their role in regulating endogenous genes. Notably, the activity of retinoic acid receptor alpha (RAR) occupied regions can either increase or decrease upon the addition of its ligand, retinoic acid, with the direction of the change correlating with spacing and orientation of the RAR consensus motif and the co-occurrence of additional sequence motifs. Together, our genome-wide enhancer activity map elucidates features associated with enhancer activity levels, identifies regulatory regions disregarded by computational prediction tools, and provides a resource for future studies into regulatory elements in mESCs.

genomics↗

bioRxiv2020

Origin, Conservation, and Loss of Alternative Splicing Events that Diversify the Proteome in Saccharomycotina Budding Yeasts

Many eukaryotes use alternative splicing to express multiple proteins from the same gene. However, while the majority of mammalian genes are alternatively spliced, other eukaryotes use this process less frequently. The budding yeast Saccharomyces cerevisiae has been successfully used to study the mechanism of splicing and the splicing machinery, but alternative splicing in yeast is relatively rare and has not been extensively studied. We have recently shown that the alternative splicing of SKI7/HBS1 is widely conserved, but that yeast and a few other eukaryotes have replaced this one alternatively spliced gene with a pair of duplicated unspliced genes as part of a whole genome doubling (WGD). Here we show that other examples of alternative splicing that were previously found to have functional consequences are widely conserved within the Saccharomycotina. We also show that the most common mechanism by which alternative splicing has disappeared is by the replacement of an alternatively spliced gene with duplicate genes. Saccharomycetaceae that diverged before WGD use alternative splicing more frequently than S. cerevisiae. This suggests that the WGD is a major reason for the low frequency of alternative splicing in yeast. We anticipate that whole genome doublings in other lineages may have had the same effect.

genetics↗