Toxicogenomic Insights into Environmental Toxicant Exposures: The TaRGET II Resource.

Environmental exposures to toxic chemicals can profoundly alter the transcriptome and epigenome in both humans and animals, contributing to disease development across the lifespan. To elucidate how early-life exposure to toxicants exerts such persistent effects, the Consortium generated a landmark resource comprising 2,570 epigenomes and 1,043 transcriptomes from longitudinal studies in mice. All data are publicly available through the TaRGET II data portal and the WashU Epigenome Browser.

Comprehensive Transcriptomic and Epigenomic Insights into Environmental Toxicant Exposures: The TaRGET II Resource.

Environmental exposures to toxic chemicals can profoundly alter the transcriptome and epigenome in both humans and animals, contributing to disease development across the lifespan. To elucidate how early-life exposure to toxicants exerts such persistent effects, the Consortium generated a landmark resource comprising 2,564 epigenomes and 1,043 transcriptomes from longitudinal studies in mice. All data are publicly available through the TaRGET II data portal and the WashU Epigenome Browser.

ToxiTaRGET: a multi-omics resource for toxicant-responsive molecular targets.

Environmental toxicant exposures can induce widespread alterations in both the transcriptome and epigenome of mammals, and directly contribute to the increased risk of various diseases, including cardiovascular disorders, cancer, and neurological disorders. To evaluate how early-life toxicants produce long-term impacts on the transcriptome and epigenome in mice, the Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription II (TaRGET II) Consortium generated a landmark resource comprising 3,607 multi-omics from longitudinal studies in mice. The molecular changes in responding to distinct environmental toxicants, including arsenic (As), lead (Pb), bisphenol A (BPA), tributyltin (TBT), di-2-ethylhexyl phthalate (DEHP), dioxin (TCDD), and fine particulate matter (PM2.

Single cell multiomics reveals drivers of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has limited treatments, and cell type-specific regulatory networks driving MASLD represent therapeutic avenues. We assayed five transcriptomic and epigenomic modalities in 2.4M cells from 86 livers across MASLD stages.

Single cell multiomics and 3D genome architecture reveal novel pathways of human heart failure.

Heart failure is a leading cause of morbidity and mortality; yet gene regulatory mechanisms driving cell type-specific pathologic responses remain undefined. Here, we present the cell type-resolved transcriptomes, chromatin accessibility, histone modifications and chromatin organization of 36 non-failing and failing human hearts profiled from 776,479 cells spanning all cardiac chambers. Integrative analyses revealed dynamic changes in cell type composition, gene regulatory programs and chromatin organization, which expanded the annotation of cardiac -regulatory sequences by ten-fold and mapped cell type-specific enhancer-gene interactions.

WashU Epigenome Browser update 2025.

The WashU Epigenome Browser (https://epigenomegateway.wustl.edu/) is a web-based tool for exploring genomic data and providing visualization, investigation, and analysis of epigenomic datasets.

Integrative Molecular and Functional Analysis of Human Sperm Subpopulations to Identify New Biomarkers of Fertilization Potential.

Background: Human ejaculates are composed of sperm subsets with heterogeneous characteristics. Comparative studies of sperm subpopulations with differences in motility may serve to investigate the functional and molecular features that are crucial for reaching the oocyte and fertilizing.

Objective: To identify functional and molecular markers that characterize sperm subpopulations with high and low motility.

Exploring the epigenome profiles of repetitive elements with the WashU Repeat Browser.

Repetitive elements, mostly derived from transposable elements (TEs), account for half the DNA in human and other mammalian genomes. Although epigenetic mechanisms, including DNA methylation and repressive histone modifications, have evolved to suppress TE activities, TEs have substantially shaped the regulatory landscape of the host genome by contributing regulatory sequences to it. TE-derived sequences are often highly repetitive and thus have low mappability, making it difficult to profile the genomics of TEs using short-read sequencing technology.

methylGrapher: genome-graph-based processing of DNA methylation data from whole genome bisulfite sequencing.

Genome graphs, including the recently released draft human pangenome graph, can represent the breadth of genetic diversity and thus transcend the limits of traditional linear reference genomes. However, there are no genome-graph-compatible tools for analyzing whole genome bisulfite sequencing (WGBS) data. To close this gap, we introduce methylGrapher, a tool tailored for accurate DNA methylation analysis by mapping WGBS data to a genome graph.

Single-cell analysis of the epigenome and 3D chromatin architecture in the human retina.

Most genetic risk variants linked to ocular diseases are non-protein coding and presumably contribute to disease through dysregulation of gene expression, however, deeper understanding of their mechanisms of action has been impeded by an incomplete annotation of the transcriptional regulatory elements across different retinal cell types. To address this knowledge gap, we carried out single-cell multiomics assays to investigate gene expression, chromatin accessibility, DNA methylome and 3D chromatin architecture in human retina, macula, and retinal pigment epithelium (RPE)/choroid. We identified 420,824 unique candidate regulatory elements and characterized their chromatin states in 23 sub-classes of retinal cells.

An integrated view of the structure and function of the human 4D nucleome.

The dynamic three-dimensional (3D) organization of the human genome (the "4D Nucleome") is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales.

Epigenetic and 3D genome reprogramming during the aging of human hippocampus.

Age-related cognitive decline is associated with altered physiology of the hippocampus. While changes in gene expression have been observed in aging brain, the regulatory mechanisms underlying these changes remain underexplored. We generated single-nucleus gene expression, chromatin accessibility, DNA methylation, and 3D genome data from 40 human hippocampal tissues spanning adult lifespan.

Epigenetic therapy potentiates transposable element transcription to create tumor-enriched antigens in glioblastoma cells.

Inhibiting epigenetic modulators can transcriptionally reactivate transposable elements (TEs). These TE transcripts often generate unique peptides that can serve as immunogenic antigens for immunotherapy. Here, we ask whether TEs activated by epigenetic therapy could appreciably increase the antigen repertoire in glioblastoma, an aggressive brain cancer with low mutation and neoantigen burden.

BAllC and BAllCools: efficient formatting and operating for single-cell DNA methylation data.

Motivation: With single-cell DNA methylation studies yielding vast datasets, existing data formats struggle with the unique challenges of storage and efficient operations, highlighting a need for improved solutions.

Results: BAllC (Binary All Cytosines) emerges as a tailored format for methylation data, addressing these challenges. BAllCools, its complementary software toolkit, enhances parsing, indexing, and querying capabilities, promising superior operational speeds and reduced storage needs.

Pycallingcards: an integrated environment for visualizing, analyzing, and interpreting Calling Cards data.

Motivation: Unraveling the transcriptional programs that control how cells divide, differentiate, and respond to their environments requires a precise understanding of transcription factors' (TFs) DNA-binding activities. Calling cards (CC) technology uses transposons to capture transient TF binding events at one instant in time and then read them out at a later time. This methodology can also be used to simultaneously measure TF binding and mRNA expression from single-cell CC and to record and integrate TF binding events across time in any cell type of interest without the need for purification.

Modbed track: Visualization of modified bases in single-molecule sequencing.

Recent advances in long-read sequencing technologies have not only dramatically increased sequencing read length but also have improved the accuracy of detecting chemical modifications to the canonical nucleotide bases, thus opening exciting venues to investigate the epigenome. Currently, the ability to visualize modified bases from long-read sequencing data in genome browsers is still limited, preventing users from easily and fully exploring these type of data. To address this limitation, the WashU Epigenome Browser introduces the modbed track type, which provides visualization of modification details in each single read as well as aggregated modifications of individual or multiple molecules across a dynamic range of resolutions.

Conserved and divergent gene regulatory programs of the mammalian neocortex.

Divergence of cis-regulatory elements drives species-specific traits, but how this manifests in the evolution of the neocortex at the molecular and cellular level remains unclear. Here we investigated the gene regulatory programs in the primary motor cortex of human, macaque, marmoset and mouse using single-cell multiomics assays, generating gene expression, chromatin accessibility, DNA methylome and chromosomal conformation profiles from a total of over 200,000 cells. From these data, we show evidence that divergence of transcription factor expression corresponds to species-specific epigenome landscapes.

Towards a comprehensive regulatory map of Mammalian Genomes.

Genome mapping studies have generated a nearly complete collection of genes for the human genome, but we still lack an equivalently vetted inventory of human regulatory sequences. Cis-regulatory modules (CRMs) play important roles in controlling when, where, and how much a gene is expressed. We developed a training data-free CRM-prediction algorithm, the Mammalian Regulatory MOdule Detector (MrMOD) for accurate CRM prediction in mammalian genomes.

BAllC and BAllCools: Efficient Formatting and Operating for Single-Cell DNA Methylation Data.

Motivation: With single-cell DNA methylation studies yielding vast datasets, existing data formats struggle with the unique challenges of storage and efficient operations, highlighting a need for improved solutions.

Results: BAllC (Binary All Cytosines) emerges as a tailored binary format for methylation data, addressing these challenges. BAllCools, its complementary software toolkit, enhances parsing, indexing, and querying capabilities, promising superior operational speeds and reduced storage needs.

TET3 plays a critical role in white adipose development and diet-induced remodeling.

Maintaining healthy adipose tissue is crucial for metabolic health, requiring a deeper understanding of adipocyte development and response to high-calorie diets. This study highlights the importance of TET3 during white adipose tissue (WAT) development and expansion. Selective depletion of Tet3 in adipose precursor cells (APCs) reduces adipogenesis, protects against diet-induced adipose expansion, and enhances whole-body metabolism.

Embryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes.

Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induce diabetes in vitamin D-sufficient mice.

Comparing genomic and epigenomic features across species using the WashU Comparative Epigenome Browser.

Genome browsers have become an intuitive and critical tool to visualize and analyze genomic features and data. Conventional genome browsers display data/annotations on a single reference genome/assembly; there are also genomic alignment viewer/browsers that help users visualize alignment, mismatch, and rearrangement between syntenic regions. However, there is a growing need for a comparative epigenome browser that can display genomic and epigenomic data sets across different species and enable users to compare them between syntenic regions.

Comparative single cell epigenomic analysis of gene regulatory programs in the rodent and primate neocortex.

Sequence divergence of regulatory elements drives species-specific traits, but how this manifests in the evolution of the neocortex at the molecular and cellular level remains to be elucidated. We investigated the gene regulatory programs in the primary motor cortex of human, macaque, marmoset, and mouse with single-cell multiomics assays, generating gene expression, chromatin accessibility, DNA methylome, and chromosomal conformation profiles from a total of over 180,000 cells. For each modality, we determined species-specific, divergent, and conserved gene expression and epigenetic features at multiple levels.

Capture Methylation-Sensitive Restriction Enzyme Sequencing (Capture MRE-Seq) for Methylation Analysis of Highly Degraded DNA Samples.

Understanding the impact of DNA methylation within different disease contexts often requires accurate assessment of these modifications in a genome-wide fashion. Frequently, patient-derived tissues stored in long-term hospital tissue banks have been preserved using formalin-fixation paraffin-embedding (FFPE). While these samples can comprise valuable resources for studying disease, the fixation process ultimately compromises the DNA's integrity and leads to degradation.