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BACKGROUND: The damaging effects of exposure to environmental toxicants differentially affect genetically distinct individuals, but the mechanisms contributing to these differences are poorly understood. Genetic variation affects the establishment of the gene regulatory landscape and thus gene expression, and we hypothesized that this contributes to the observed heterogeneity in individual responses to exogenous cellular insults. OBJECTIVES: We performed an in vivo study of how genetic variation and chromatin organization may dictate susceptibility to DNA damage, and influence the cellular response to such damage, caused by an environmental toxicant. MATERIALS AND METHODS: We measured DNA damage, messenger RNA (mRNA) and microRNA (miRNA) expression, and genome-wide chromatin accessibility in lung tissue from two genetically divergent inbred mouse strains, C57BL/6J and CAST/EiJ, both in unexposed mice and in mice exposed to a model DNA-damaging chemical, 1,3-butadiene. RESULTS: Our results showed that unexposed CAST/EiJ and C57BL/6J mice have very different chromatin organization and transcription profiles in the lung. Importantly, in unexposed CAST/EiJ mice, which acquired relatively less 1,3-butadiene-induced DNA damage, we observed increased transcription and a more accessible chromatin landscape around genes involved in detoxification pathways. Upon chemical exposure, chromatin was significantly remodeled in the lung of C57BL/6J mice, a strain that acquired higher levels of 1,3-butadiene-induced DNA damage, around the same genes, ultimately resembling the molecular profile of CAST/EiJ. CONCLUSIONS: These results suggest that strain-specific changes in chromatin and transcription in response to chemical exposure lead to a "compensation" for underlying genetic-driven interindividual differences in the baseline chromatin and transcriptional state. This work represents an example of how chemical and environmental exposures can be evaluated to better understand gene-by-environment interactions, and it demonstrates the important role of chromatin response in transcriptomic changes and, potentially, in deleterious effects of exposure. [ABSTRACT FROM AUTHOR]

Pif1 family helicases are found in virtually all eukaryotes. Saccharomyces cerevisiae (Sc) encodes two Pif1 family helicases, ScPif1 and Rrm3. ScPif1 is multifunctional, required not only for maintenance of mitochondrial DNA but also for multiple distinct nuclear functions. Rrm3 moves with the replication fork and promotes movement of the fork through 1400 hard-to-replicate sites, including centromeres. Here we show that ScPif1, like Rrm3, bound robustly to yeast centromeres but only if the centromere was active. While Rrm3 binding to centromeres occurred in early to mid S phase, about the same time as centromere replication, ScPif1 binding occurred later in the cell cycle when replication of most centromeres is complete. However, the timing of Rrm3 and ScPif1 centromere binding was altered by the absence of the other helicase, such that Rrm3 centromere binding occurred later in pif1-m2 cells and ScPif1 centromere binding occurred earlier in rrm3D cells. As shown previously, the modest pausing of replication forks at centromeres seen in wild-type cells was increased in the absence of Rrm3. While a lack of ScPif1 did not result in increased fork pausing at centromeres, pausing was even higher in rrm3D pif1D cells than in rrm3D cells. Likewise, centromere function as monitored by the loss rate of a centromere plasmid was increased in rrm3D but not pif1D cells, and was even higher in rrm3D pif1D cells than in rrm3D cells. Thus, ScPif1 promotes centromere replication and segregation, but only in the absence of Rrm3. These data also hint at a potential post-S phase function for ScPif1 at centromeres. These studies add to the growing list of ScPif1 functions that promote chromosome stability. [ABSTRACT FROM AUTHOR]

A conference paper about the role of histone modifications to regulate nucleosome dynamics is presented. It focuses on the understanding the influence on nucleosome structure due to deoxyribonucleic acid (DNA) like structure. It examines the modifications in the nucleosomal core such as H3K122ac, a residue at the lateral surface, as a novel acetylation site, to stimulate transcription by modulating histone-DNA binding in regulating chromatin function.

Summary: The transcription factor early B cell factor-1 (Ebf1) is a key determinant of B lineage specification and differentiation. To gain insight into the molecular basis of Ebf1 function in early-stage B cells, we combined a genome-wide ChIP sequencing analysis with gain- and loss-of-function transcriptome analyses. Among 565 genes that are occupied and transcriptionally regulated by Ebf1, we identified large sets involved in (pre)-B cell receptor and Akt signaling, cell adhesion, and migration. Interestingly, a third of previously described Pax5 targets was found to be occupied by Ebf1. In addition to Ebf1-activated and -repressed genes, we identified targets at which Ebf1 induces chromatin changes that poise the genes for expression at subsequent stages of differentiation. Poised chromatin states on specific targets could also be established by Ebf1 expression in T cells but not in NIH 3T3 cells, suggesting that Ebf1 acts as a “pioneer” factor in a hematopoietic chromatin context. [Copyright &y& Elsevier]