Biology subjects

Sonder, E.

Publications and source records attributed to Sonder, E..

6 recordsLinked to original sources

bioRxiv2026

Addressing technical variations in ATAC-seq data and improving motif accessibility analyses

Tagmentation-based methods such as ATAC-seq and Cut&Tag have provided easy ways to profile the epigenome in low-input samples and even single cells. In this contribution, we discuss forms of bias (i.e. technical variations) in tagmentation-based data, in particular ATAC-seq, and introduce three R/bioconductor packages to facilitate bulk and single-cell epigenomic data analysis, with a special focus on motif accessibility analysis. The weightedMotifAccess package uses weight models to enable motif accessibility analysis, including transcription factor footprint information. The betterChromVAR package provides a novel, analytical re-implementation of the popular chromVAR method that offers substantial speed improvements, eliminates stochasticity, and offers additional features. Based on this, we also propose a method, CVnorm, that outperforms alternatives in normalizing technical bias in peak count data. The computational efficiency of these tools further enables a new framework for systematically investigating synergistic and antagonistic interactions between transcription factor motifs. Finally, the epiwraps package streamlines the visualization, normalization, and summarization of epigenomic data.

bioinformatics↗

bioRxiv2026

Large-scale prediction of transcription factor binding across human cell types informs regulatory genomics and reveals promiscuous occupancy associated with chromatin contacts

Our understanding of the mechanisms regulating gene expression has been hampered by our limited knowledge of which transcription factors (TFs) bind where in the genome, which is highly cell type-specific. While genome-wide TF binding can be experimentally assayed for individual TFs in individual cell types, profiling the full combinations of over 1600 TFs in hundreds of cell types is beyond practical reach. In this work, we developed a streamlined platform, TFBlearner, to train TF-specific models and predict bindings based on ATAC-seq data. We focused on biologically-motivated feature engineering and harnessed TF cooperativity and binding similarity across cell types to achieve state of the art binding predictions in unseen cell types in a scalable fashion. This enabled us to generate a compendium of binding predictions for 1108 Chromatin-associated proteins, of which 960 TFs, across 43 human cell types including widely-used cell lines and 36 physiological cell types representing all major human cell lineages. We show how the models additionally provide biological insights on the TFs, and show how the binding predictions can be used in downstream tasks such as TF activity inference. Our study additionally led to the observation of high promiscuity in TF occupancy. To investigate aspecific occupancy, we characterized crowded or high-occupancy (HOT) regions across cell types, providing evidence of their functionality, and reporting important cell type-specificity. Finally, we show that, across cell types, crowded regions engage in more 3D contacts, and that most TF occupancy at crowded promoters can be explained as tethered bindings from distal regulatory elements.

genomics↗

bioRxiv2025

Distinct molecular mechanisms of stress habituation in the mouse hippocampus

Chronic stress is a risk factor for neuropsychiatric disorders, making the ability to adapt to repeated stress a crucial determinant of mental health. On a molecular level, it remains unclear whether repeated exposure to stress is characterized by habituation - a decreased responsiveness to the same stimulus - or by the emergence of new, adaptive responses. Here, we explore how the tightly regulated molecular response triggered by acute restraint stress becomes altered after repeated restraint exposure. Transcriptomic sampling of the mouse hippocampus at multiple time points revealed that repeated stress leads to widespread habituation, damping stress-induced gene expression of all stress-responsive genes. However, we find no evidence for the emergence of new response profiles or alterations in baseline gene expression. Using single-cell multi-omics, we show that these findings hold true across cell types, and we reveal cell type specific patterns of habituation. Transcriptomic and chromatin accessibility profiles identify two distinct mechanisms that contribute to the observed habituation patterns: an early cAMP-associated mechanism that is related to blunted transcription after chronic stress, and a late corticosterone-dependent mechanism that is linked to a shortened transcriptional response. These extensive data are integrated, along with our previous work, into an interactive app, providing a uniquely detailed molecular resource that characterizes the acute stress response and the process of habituation across the genome.

neuroscience↗

bioRxiv2024

On the identification of differentially-active transcription factors from ATAC-seq data

ATAC-seq has emerged as a rich epigenome profiling technique, and is commonly used to identify Transcription Factors (TFs) underlying given phenomena. A number of methods can be used to identify differentially-active TFs through the accessibility of their DNA-binding motif, however little is known on the best approaches for doing so. Here we benchmark several such methods using a combination of curated datasets with various forms of short-term perturbations on known TFs, as well as semi-simulations. We include both methods specifically designed for this type of data as well as some that can be repurposed for it. We also investigate variations to these methods, and identify three particularly promising approaches (a chromVAR-limma workflow with critical adjustments, monaLisa and a combination of GC smooth quantile normalization and multivariate modeling). We further investigate the specific use of nucleosome-free fragments, the combination of top methods, and the impact of technical variation. Finally, we illustrate the use of the top methods on a novel dataset to characterize the impact on DNA accessibility of TRAnscription Factor TArgeting Chimeras (TRAFTAC), which can deplete TFs - in our case NFkB - at the protein level. Author summaryTranscription factors regulate gene expression by binding sites in the genome that often harbor a specific DNA motif. The collective accessibility of these motif-matching regions, measured by technologies such as ATAC-seq, can be used to infer the activity of the corresponding transcription factors. Here we use curated datasets of 11 TF-specific perturbations as well as 116 semi-simulated datasets to benchmark various methods for identifying factors that differ in activity between experimental conditions. We investigate important variations in the analysis and make recommendations pertaining to such analysis. Finally, we illustrate the application of the top methods to characterize the effects of a novel method for perturbing transcription factors at the protein level.

bioinformatics↗

bioRxiv2023

Validation of hypermethylated DNA regions found in colorectal cancers as potential aging-independent biomarkers of precancerous colorectal lesions

BackgroundWe previously identified 16,772 colorectal cancer-associated hypermethylated DNA regions that were also detectable in precancerous colorectal lesions (preCRCs) and unrelated to normal mucosal aging. We have now conducted a study to validate 990 of these differentially methylated DNA regions (DMR) in a new series of preCRCs. MethodsWe used targeted bisulfite sequencing to validate these 990 potential biomarkers in 59 preCRC tissue samples (41 conventional adenomas, 18 sessile serrated lesions), each with a patient-matched normal mucosal sample. Based on differential DNA methylation tests, a panel of (candidate) DMRs was chosen on a subset of the (our) cohort and validated on the remaining part of our cohort and (two) further publicly available datasets with respect to their stratifying potential between preCRCs and normal mucosa. ResultsStrong statistical significance for the difference in methylation levels was observed across the full set of 990 investigated DMRs. From these, a selected candidate panel of 30 DMRs correctly identified 58/59 tumors (area under the receiver operating curve: 0.998). ConclusionsThese validated DNA hypermethylation markers can be exploited to develop more accurate noninvasive colorectal tumor screening assays.

genomics↗

bioRxiv2022

Meta-analysis of (single-cell method) benchmarks reveals the need for extensibility and interoperability

Computational methods represent the lifeblood of modern molecular biology. Benchmarking is important for all methods, but with a focus here on computational methods, benchmarking is critical to dissect important steps of analysis pipelines, formally assess performance across common situations as well as edge cases, and ultimately guide users on what tools to use. Benchmarking can also be important for community building and advancing methods in a principled way. We conducted a meta-analysis of recent single-cell benchmarks to summarize the scope, extensibility, neutrality, as well as technical features and whether best practices in open data and reproducible research were followed. The results highlight that while benchmarks often make code available and are in principle reproducible, they remain difficult to extend, for example, as new methods and new ways to assess methods emerge. In addition, embracing containerization and workflow systems would enhance reusability of intermediate benchmarking results, thus also driving wider adoption.

bioinformatics↗