Genetic variation in the Y chromosome and sex-biased DNA methylation in somatic cells in the mouse.

Several lines of evidence suggest that the presence of the Y chromosome influences DNA methylation of autosomal loci. To better understand the impact of the Y chromosome on autosomal DNA methylation patterns and its contribution to sex bias in methylation, we identified Y chromosome dependent differentially methylated regions (yDMRs) using whole-genome bisulfite sequencing methylation data from livers of mice with different combinations of sex-chromosome complement and gonadal sex. Nearly 90% of the autosomal yDMRs mapped to transposable elements (TEs) and most of them had lower methylation in XY compared to XX or XO mice. Follow-up analyses of four reporter autosomal yDMRs showed that Y-dependent methylation levels were consistent across most somatic tissues but varied in strains with different origins of the Y chromosome, suggesting that genetic variation in the Y chromosome influenced methylation levels of autosomal regions. Mice lacking the q-arm of the Y chromosome (B6.NPYq-2) as well as mice with a loss-of-function mutation in Kdm5d showed no differences in methylation levels compared to wild type mice. In conclusion, the Y-linked modifier of TE methylation is likely to reside on the short arm of Y chromosome and further studies are required to identify this gene.

Five multicopy gene family genes expressed during the maternal-to-zygotic transition are not essential for mouse development.

Upon fertilization, oocytes transform into totipotent and pluripotent cleavage stage cells through the maternal-to-zygotic transition (MZT), which is regulated by maternal factors and zygotic genome activation (ZGA). Here, we investigated the in vivo function of 16 genes expressed with strong biases in oocytes and cleavage stage embryos by generating knockout (KO) mice. These MZT-associated genes are conserved across many mammalian species and include five multicopy gene family genes: the Nlrp9, Khdc1, Rfpl4, Trim43, and Zscan5 genes. Intercrosses between female KO and male KO mice, including Nlrp9a/b/c triple KO (TKO), Khdc1a/b/c TKO, Rfpl4a/b double KO (DKO), Trim43a/b/c TKO, and Zscan5b KO mice led to the birth to healthy offspring that in turn produced healthy offspring. Our study not only demonstrated that these MZT-associated genes are not essential for mouse development, but also provides valuable resources for analyzing the functions of these genes in other genetic backgrounds, in the presence of stressors, and under pathogenic conditions.

Prognostic stratification of patients with nasopharyngeal carcinoma based on tumor immune microenvironment.

BACKGROUND: Little is known about immune-related prognostic factors in patients with nasopharyngeal carcinoma (NPC). METHODS: We retrospectively reviewed 66 patients with NPC. Epstein-Barr virus (EBV) status, programmed cell death-ligand 1 (PD-L1) expression, and tumor-infiltrating lymphocyte (TIL) densities were analyzed, and a prognostic evaluation of these immune-related parameters was performed. RESULTS: The multivariate analyses demonstrated that CD8-positive TIL density but not PD-L1 expression on tumor cells or immune cells was a significant predictive factor for progression-free survival (PFS) and overall survival (OS). Subgroup analyses demonstrated that a positive PD-L1 expression on tumor cells in combination with a higher CD8-positive TIL density was significantly associated with favorable prognosis, whereas positive PD-L1 expression on tumor cells with lower CD8-positive TIL density was associated with worse prognosis. CONCLUSION: Our results suggest that PD-L1 expression on tumor cells in combination with CD8-positive TIL density could be a useful predictive biomarker for risk stratification in patients with NPC.