A time-series analysis of altered histone H3 acetylation and gene expression during the course of MMAIII-induced malignant transformation of urinary bladder cells.

Abstract

Our previous studies have shown that chronic exposure to low doses of monomethylarsonous acid (MMAIII) causes global histone acetylation dysregulation in urothelial cells (UROtsa cells) during the course of malignant transformation. To reveal the relationship between altered histone acetylation patterns and aberrant gene expression, more specifically, the carcinogenic relevance of these alterations, we performed a time-course analysis of the binding patterns of histone 3 lysine 18 acetylation (H3K18ac) across the genome and generated global gene-expression profiles from this UROtsa cell malignant transformation model. We showed that H3K18ac, one of the most significantly upregulated histone acetylation sites following MMAIII exposure, was enriched at gene promoter-specific regions across the genome and that MMAIII-induced upregulation of H3K18ac led to an altered binding pattern in a large number of genes that was most significant during the critical window for MMAIII-induced UROtsa cells' malignant transformation. Some genes identified as having a differential binding pattern with H3K18ac, acted as upstream regulators of critical gene networks with known functions in tumor development and progression. The altered H3K18ac binding patterns not only led to changes in expression of these directly affected upstream regulators but also resulted in gene-expression changes in their regulated networks. Collectively, our data suggest that MMAIII-induced alteration of histone acetylation patterns in UROtsa cells led to a time- and malignant stage-dependent aberrant gene-expression pattern, and that some gene regulatory networks were altered in accordance with their roles in carcinogenesis, probably contributing to MMAIII-induced urothelial cell malignant transformation and carcinogenesis.