Biology subjects

Bartolomei, M.

Publications and source records attributed to Bartolomei, M..

3 recordsLinked to original sources

bioRxiv2025

The impact of environmental exposures on the epigenomic and transcriptomic landscape of transposable elements

Transposable elements (TEs) are mobile DNA sequences that constitute a significant portion of mammalian genomes. While typically silenced by epigenetic mechanisms, mounting evidence indicates TEs can regulate gene expression and chromatin architecture. However, their regulatory roles under various environmental exposures remain largely unexplored. In this study, we investigate the regulatory functions of TEs in mouse liver tissue following early-life exposure to environmental toxicants, including arsenic (As), lead (Pb), bisphenol A (BPA), tributyltin (TBT), di-2-ethylhexyl phthalate (DEHP), tetrachlorodibenzo-p-dioxin (TCDD), and particulate matter less than 2.5 micrometers (PM2.5). These toxicants are linked to various health issues, including neurodevelopmental deficits, metabolic and immune dysfunction, and increased cancer risks. Integrative analysis of 351 multi-omics datasets from liver tissues of 5-month-old mice indicated that early-life environmental exposures significantly altered chromatin accessibility and expression of TEs in later life stage, revealing distinct exposure-specific signatures and sex-dependent responses. 6,699 TEs were identified with altered chromatin accessibility, mostly in non-coding regions, suggesting potential impact on gene regulation. Within these TEs, LINE elements were enriched in genes involved in metabolic pathways, while LTR elements, particularly the ORR1E subfamily, were predominantly associated with immune-related genes. Additionally, we identified 140 TE-gene chimeric transcripts with TE-derived novel transcription start sites, highlighting TE-contributed transcriptional plasticity. Our findings depict a comprehensive landscape of TE regulation under early-life toxicant exposures, offering insights into TEs biology and their impact on health and disease.

genomics↗

bioRxiv2025

Sparse Sequencing permits accurate and efficient quantification of genome-wide cytosine modification levels

5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) regulate gene expression and exhibit dynamic levels during development and disease. While high-depth, base-resolution studies offer the most detailed view of epigenetic landscapes, many open questions are answered by surveying changes in 5mC/5hmC levels across larger cohorts. Nonetheless, current global quantification methods, including mass spectrometry, are typically limited in accessibility, accuracy, or throughput. Here, to evaluate the viability of low-coverage sequencing as an alternative, we first computationally downsampled deeply sequenced data to resolve the three-way relationship between sequencing coverage, modification levels, and measurement error. This relationship allowed us to develop a facile online tool for error calculation and to define experimental targets: <0.24% genome coverage can quantify 5mC and low-abundance 5hmC with minimal and predictable errors (<5%). Importantly, in direct comparisons, low-depth sequencing (Sparse-Seq) demonstrated high accuracy and less variability than mass spectrometry, while distinctively preserving genomic context. Applied serially to developing mouse brains, Sparse-Seq revealed an earlier emergence of 5hmCpG compared to 5mCpH and uncovered previously overlooked, genomic feature-specific epigenetic changes. This work establishes a rigorous foundation for employing Sparse-Seq as a highly accessible approach for 5mC/5hmC quantification, enabling economical first-pass analysis of epigenetic landscapes suited for large cohort studies and new hypothesis generation.

genomics↗

bioRxiv2023

TET1 Catalytic Activity is Required for Reprogramming of Imprinting Control Regions and Patterning of Sperm-Specific Hypomethylated Regions

DNA methylation erasure is required for mammalian primordial germ cell reprogramming. TET enzymes iteratively oxidize 5-methylcytosine to generate 5-hyroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxycytosine to facilitate active genome demethylation. Whether these bases are required to promote replication-coupled dilution or activate base excision repair during germline reprogramming remains unresolved due to the lack of genetic models that decouple TET activities. Here, we generated two mouse lines expressing catalytically inactive TET1 (Tet1-HxD) and TET1 that stalls oxidation at 5hmC (Tet1-V). Tet1-/-, Tet1V/V, and Tet1HxD/HxD sperm methylomes show that TET1V and TET1HxD rescue most Tet1-/- hypermethylated regions, demonstrating the importance of TET1s extra-catalytic functions. Imprinted regions, in contrast, require iterative oxidation. We further reveal a broader class of hypermethylated regions in sperm of Tet1 mutant mice that are excluded from de novo methylation during male germline development and depend on TET oxidation for reprogramming. Our study underscores the link between TET1-mediated demethylation during reprogramming and sperm methylome patterning.

developmental biology↗