Discovery And Functional Genomics Of Environmental Response Genes

National Institute Of Environmental Health Sciences

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Abstract

P53 project. The p53 tumor suppressor protein is a master regulatory transcription factor that coordinates cellular responses to DNA damage and other sources of cellular stress. Besides mutations in p53, or in proteins involved in the p53 response pathway, genetic variation in promoter response elements (REs) of individual p53 target genes are expected to alter biological responses to stress. We analyzed stress-induced changes of p53 binding, chromatin state, and gene expression after treating human lymphoblastoid cells with the DNA-damaging agent doxorubicin and then mapping p53 binding and the chromatin activation mark, H3K4me3, by ChIP-seq. Characterizing the chromatin-mediated p53 stress response and the deregulation of transposons may prove to be clinically relevant for understanding outcomes in cytotoxic therapy for cancer (Su et al PLoS Gen). These studies reveal a functional link between variation in p53RE sequence and chromatin accessibility that seems to have been tuned via evolutionary selection pressure. (Millau et al 2011, Bandele et al, 2011, Zeron-Medina et al Cell, 2013, Azzam et al 2013, Jennis et al 2016, Stracquadanio et al 2016). Zhang et al Inherited and somatic genetic variants in the p53 pathway interact to affect cancer risk and progression. Defining the somatic mutations that drive cancer has improved precision oncology. Here, by integrating germline datasets relating to cancer susceptibility with tumour data capturing somatically-acquired genetic variation, we provide evidence that single nucleotide polymorphism (SNPs) and somatic mutations in the p53 tumor suppressor pathway can interact to influence cancer development, progression and treatment response. We go on to provide human genetic evidence of a tumor-promoting role for the pro-survival activities of p53, which supports the development of more effective therapy combinations through their inhibition in cancers retaining wild-type p53. Significance. Insights into oncogenesis derived from cancer susceptibility loci could facilitate better cancer management and treatment through precision oncology. However, therapeutic applications have thus far been limited by our current lack of understanding regarding both their interactions with somatic cancer driver mutations and their influence on tumorigenesis. Here, we describe significant interactions between heritable and somatic genetic variants in the p53 pathway that affect cancer susceptibility, progression and treatment response. Our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel therapeutic targets. Single-cell analyses identify dysfunctional CD16+ CD8 T cells in smokers (Martos et al, 2020)SUMMARY: Tobacco smoke exposure impacts immune response, leukocyte subtypes, DNA methylation, and gene expression. We performed single-cell RNA sequencing (scRNAseq) on >45,000 human peripheral blood immune cells from smokers and nonsmokers. Transcriptomes revealed a subpopulation of FCGR3A (CD16)-expressing Natural Killer (NK)-like T lymphocytes that increased in smokers. Mass cytometry confirmed an increase in the frequency of CD16+ CD8 T cells in smokers. The majority of CD16+ CD8 T cells were CD45RA positive, indicating an effector memory re-expressing CD45RA T cell (TEMRA) phenotype. Smokers CD8 T cells were biased toward differentiated cells and had a lower frequency of nave cells, an indication of immune aging. FCGR3A-expressing CD8 T cells were inferred as the most differentiated cluster and expressed senescence markers. Smokers expressed senescence-linked genes in other immune populations and had elevated Tregs, which induce senescence. Our results suggest that smoking-induced, senescence-associated immune cell dysregulation contributes to smoking-mediated pathologies.