Histone Modification Profiling Reveals Trichloroethylene Metabolite-Driven Epigenetic Remodeling and Associated Changes in Cell Cycle Progression in Activated CD4+ T Cells from Autoimmune-Prone MRL/MpJ Mice

Author

• Laura V. Santos-Medina, The University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM 87131, USAFollow

Publication Date

Summer 7-28-2026

Abstract

Environmental toxicants such as trichloroethylene (TCE) contribute to immune dysregulation and autoimmunity, yet underlying epigenetic mechanisms remain unclear. Prior work identified DNA methylation changes in CD4⁺ T cells at histone-related genes and Polycomb targets following TCE/trichloroacetaldehyde hydrate (TCAH) exposure, suggesting additional epigenetic mechanisms. Naïve CD4⁺ T cells from autoimmune-prone MRL/MpJ mice were activated with ±0.5 mM TCAH for four days. Histone PTMs were quantified by mass spectrometry, and DNA methylation at heterochromatin repeats D4Z4 and NBL2 was assessed by pyrosequencing. TCAH induced widespread PTM remodeling. H3.1 regions remained stable, whereas H3.3 domains showed reduced H3K27me3 and increased H3K36me2/3, consistent with loss of methylation restraint and enhanced transcription. DNA methylation analysis revealed hypomethylation at D4Z4 and hypermethylation at NBL2, indicating a compensatory mechanism to restore loss of methylation of H3K27me3 and irregular methylation patterns at CpG island repeats independent of location. Cell cycle analysis showed altered phase distribution, consistent with altered chromatin states and faulty transcriptional signals. Overall, TCAH disrupts epigenetic regulation in a histone variant- and locus-specific manner, potentially contributing to transcriptional and cell cycle dysregulation in CD4⁺ T cells.

TCAH induced widespread PTM remodeling. H3.1 regions remained stable, whereas H3.3 domains showed reduced H3K27me3 and increased H3K36me2/3, consistent with loss of methylation restraint and enhanced transcription. DNA methylation analysis revealed hypomethylation at D4Z4 and hypermethylation at NBL2, indicating a compensatory mechanism to restore loss of methylation of H3K27me3 and irregular methylation patterns at CpG island repeats independent of location. Cell cycle studies suggested dysregulated phase distribution in C57BL/6 and MRL/MpJ mice, consistent with altered chromatin states and faulty transcriptional signals. Overall, TCAH disrupts epigenetic regulation in a histone variant- and locus-specific manner, potentially contributing to transcriptional and cell cycle dysregulation in CD4⁺ T cells and ultimately promoting aberrant immune activation and loss of self-tolerance, key processes underlying the development of autoimmune diseases.

Keywords

Immunotoxicology, trichloroethylene, autoimmune, CD4 T cells, environmental toxicants

Document Type

Thesis

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Masters

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Dr. Sebastian Medina

Second Committee Member

Dr. Sarah Blossom

Third Committee Member

Dr. Alicia Bolt

Recommended Citation

Santos-Medina, Laura V.. "Histone Modification Profiling Reveals Trichloroethylene Metabolite-Driven Epigenetic Remodeling and Associated Changes in Cell Cycle Progression in Activated CD4+ T Cells from Autoimmune-Prone MRL/MpJ Mice." (2026). https://digitalrepository.unm.edu/biom_etds/321