TET1 regulates responses to house dust mite by altering chromatin accessibility, DNA methylation, and gene expression in airway epithelial cells.

ABSTRACT

Background: Previous studies have identified TET1 as a potential key regulator of genes linked to asthma. TET1 has been shown to transcriptionally respond to house dust mite extract, an allergen known to directly cause allergic asthma development, and regulate the expression of genes involved in asthma. How TET1 regulates expression of these genes, however, is unknown. TET1 is a DNA demethylase; therefore, most prior research on TET1-based gene regulation has focused on how TET1 affects methylation. However, TET1 can also interact directly with transcription factors and histone modifiers to regulate gene expression. Understanding how TET1 regulates expression to contribute to allergic responses and asthma development thus requires a comprehensive approach. To this end, we measured mRNA expression, DNA methylation, chromatin accessibility and histone modifications in control and TET1 knockdown human bronchial epithelial cells treated or untreated with house dust mite extract. Results: Throughout our analyses, we detected strong similarities between the effects of TET1 knockdown alone and the effects of HDM treatment alone. One especially striking pattern was that both TET1 knockdown and HDM treatment generally led to decreased chromatin accessibility at largely the same genomic loci. Transcription factor enrichment analyses indicated that altered chromatin accessibility following the loss of TET1 may affect, or be affected by, CTCF and CEBP binding. TET1 loss also led to changes in DNA methylation, but these changes were generally in regions where accessibility was not changing. Conclusions: TET1 regulates gene expression through different mechanisms (DNA methylation and chromatin accessibility) in different parts of the genome in the airway epithelial cells, which mediates inflammatory responses to allergen. Collectively, our data suggest novel molecular mechanisms through which TET1 regulates critical pathways following allergen challenges and contributes to the development of asthma.