Analysis of Binding of KIR3DS1*014 to HLA Suggests Distinct Evolutionary History of KIR3DS1

NK cell activity is regulated by the integration of positive and negative signals. One important source of these signals for human NK cells is the killer Ig-like receptor (KIR) family, which includes both members that transduce positive and those that generate negative signals. KIR3DL1 inhibits NK cell activity upon engagement by its ligand HLA-Bw4. The highly homologous KIR3DS1 is an activating receptor, which is implicated in the outcome of a variety of pathological situations. However, unlike KIR3DL1, direct binding of KIR3DS1+ cells to HLA has not been demonstrated. We analyzed four key amino acid differences between KIR3DL1*01502 and KIR3DS1*013 to determine their role in KIR binding to HLA. Single substitutions of these residues dramatically reduced binding by KIR3DL1. In the reciprocal experiment, we found that the rare KIR3DS1 allotype KIR3DS1*014 binds HLA-Bw4 even though it differs from KIR3DS1*013 at only one of these positions (position 138). This reactivity was unexpectedly dependent on residues at other variable positions, as HLA-Bw4 binding was lost in receptors with KIR3DL1-like residues at both positions 199 and 138. These data provide the first evidence, to our knowledge, for the direct binding of KIR3DS1+ cells to HLA-Bw4 and highlight the key role for position 138 in determining ligand specificity of KIR3DS1. They also reveal that KIR3DS1 reactivity and specificity is dictated by complex interactions between the residues in this region, suggesting a unique functional evolution of KIR3DS1 within the activating KIR family

A Review of Dietary Prevention of Human Papillomavirus-Related Infection of the Cervix and Cervical Intraepithelial Neoplasia

The natural history of cervical cancer suggests that prevention can be achieved by modification of the host's immune system through a nutrient-mediated program. This study reviews the preventive role of dietary intake on cervical intraepithelial neoplasia (CIN) induced by human papillomavirus (HPV). Electronic databases were searched using relevant keywords such as, but not limited to, human papillomavirus infection, cervical intraepithelial neoplasia, lifestyle factors, nutrients intake, and diet. High consumption of fruit and vegetables appears to be protective against CIN. The findings also highlight the possibility of consuming high levels of specific nutrients, vitamins, and minerals, and retaining sufficient level of these elements in the body, especially those with high antioxidants and antiviral properties, to prevent progression of transient and persistent HPV infections to high-grade CIN 2 and 3 (including in situ cervical cancer). The protective effect is not significant for high-risk HPV persistent infections and invasive cervical cancer. Although it appears that intake of specific nutrients, vitamins, and minerals may be good in CIN prevention, there is lack of evidence from controlled trial to confirm this. Health professionals shall focus on implementation of a balanced-diet prevention strategy at an early stage for cervical cancer prevention

Chromatin accessibility and epigenetic changes induced by xenobiotic and hormone exposure in young adult mouse liver

Transcription factors activated by exogenous or endogenous stimuli alter gene expression with major effects on chromatin accessibility and the epigenome. This thesis investigates that impact of environmental chemical and hormonal exposure on liver chromatin accessibility in a mouse liver model. Exposure to the constitutive androstane receptor (CAR)-specific agonist ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) induces localized changes in chromatin accessibility at several thousand DNase hypersensitive sites (DHS). Activating histone marks, associated with enhancers and promoters, were induced by TCPOBOP and were highly enriched at opening DHS. Opening DHS were highly enriched for CAR binding sites and nuclear receptor direct repeat-4 motifs. These DHS were also enriched for the CAR heterodimeric partner RXRA, binding by CEBPA and CEBPB, and motifs for other liver-specific factors. Thus, TCPOBOP alters the enhancer landscape through changes in histone marks and by mechanisms linked to induced CAR binding. In other studies, the impact of pituitary growth hormone (GH) secretion patterns on chromatin accessibility changes associated with sex-biased liver gene expression was examined. In adult male liver, the transcription factor STAT5 is directly activated by each successive plasma GH pulse. In female liver, STAT5 is persistently activated by the near-continuous stimulation by plasma GH. A majority of the ~4,000 GH-regulated, sex-biased DHS have chromatin marks characteristic of enhancers and were enriched for proximity to sex-biased gene promoters. Chromatin accessibility is thus a key feature of sex-differential gene expression. Two major classes of male-biased DHS were identified: dynamic male-biased DHS, almost all bound by STAT5, which undergo repeated cycles of chromatin opening and closing induced by each GH pulse; and static male-biased DHS, whose accessibility is unaffected GH/STAT5 pulses and whose sex bias results from these chromatin sites being more closed in female liver. Sites with STAT5 binding showed greater chromatin opening, many of which also contain the STAT5 motif. Finally, the effect of a single GH pulse on hypophysectomized male mouse liver was investigated to identify DHS responsive to the male, pulsatile-GH, secretion pattern. These studies demonstrate that widespread epigenetic changes associated with target gene expression are induced by xenobiotics and hormones regulating liver gene expression.2022-01-31T00:00:00

Table_S2FGHI_Rampersaud_ToxSci_2019

Supplemental Table S2FGHI, related to Rampersaud et al, Toxicological Sciences, 201

Table_S4_Rampersaud_ToxSci_2019

Supplemental Table S4, related to Rampersaud et al, Toxicological Sciences, 201

Table_S6_Rampersaud_ToxSci_2019

Supplemental Table S6, related to Rampersaud et al, Toxicological Sciences, 201

Data from: Widespread epigenetic changes to the enhancer landscape of mouse liver induced by a specific xenobiotic agonist ligand of the nuclear receptor CAR

CAR (Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid and lipid metabolism and dysregulates genes linked to hepatocellular carcinogenesis, but its impact on the liver epigenome is poorly understood. TCPOBOP, a halogenated xenochemical and highly specific CAR agonist ligand, induces localized chromatin opening or closing at several thousand mouse liver genomic regions, discovered as differential DNase-hypersensitive sites (ΔDHS). Active enhancer and promoter histone marks induced by TCPOBOP were enriched at opening DHS and TCPOBOP-inducible genes. Enrichment of CAR binding and CAR motifs was seen at opening DHS and their inducible drug/lipid metabolism gene targets, and at many constitutively open DHS located nearby. TCPOBOP-responsive cell cycle and DNA replication genes co-dependent on MET/EGFR signaling for induction were also enriched for CAR binding. A subset of opening DHS and many closing DHS mapping to TCPOBOP-responsive target genes did not bind CAR, indicating an indirect mechanism for their changes in chromatin accessibility. TCPOBOP-responsive DHS were also enriched for induced binding of RXRA, CEBPA and CEBPB, and for motifs for liver-enriched factors that may contribute to liver-specific transcriptional responses to TCPOBOP exposure. These studies elucidate the enhancer landscape of TCPOBOP-exposed liver and the widespread epigenetic changes that are induced by both direct and indirect mechanisms linked to CAR activation. The global maps of thousands of environmental chemical-induced epigenetic changes described here constitute a rich resource for further research on xenochemical effects on liver chromatin states and the epigenome

Table_S2CDE_Rampersaud_ToxSci_2019

Supplemental Table S2CDE, related to Rampersaud et al, Toxicological Sciences, 201

Table_S5_Rampersaud_ToxSci_2019

Supplemental Table S5, related to Rampersaud et al, Toxicological Sciences, 201

Table_S3_Rampersaud_ToxSci_2019

Supplemental Table S3, related to Rampersaud et al, Toxicological Sciences, 201