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PNAS Papers Examine Prostate Cancer Splicing, Arabidopsis Methylation, X Chromosome Dosage Effects

Researchers from the University of California, Los Angeles, and elsewhere describe an apparent role for the cancer-related gene Myc in alternative splicing regulation in prostate cancer, identified in a pre-messenger RNA splicing analysis. With the help of mRNA splicing analysis software called rMATS-turbo, the team analyzed RNA sequencing data for nearly 900 samples — including primary prostate adenocarcinomas, metastatic, castration-resistant adenocarcinomas, treatment-related neuroendocrine prostate cancers, and benign tumor-adjacent prostate tissue samples — uncovering thousands of exon events that were subsequently considered in the context of cancer-related pathways. "Through computational and experimental studies, we found that a strong cancer driver gene, Myc, was linked to exon changes in genes that themselves regulate alternative splicing," the authors report, hinting that Myc may contribute to an "autoregulatory loop" influencing splicing regulatory protein levels.

A University of Georgia team takes a look at DNA methylation variation across packed heterochromatin and active euchromatin regions in the genome for hundreds of different Arabidopsis thaliana accessions. With bisulfite sequencing data for 725 A. thaliana accessions, the researchers mapped variable DNA methylation events. Among other things, they saw heterochromatin-related shifts in DNA methylation that varied between accessions, pointing to the presence of DNA methylation epialleles in the model plant. "Plant genotypes that had lower levels of methylation in heterochromatin had more genes with DNA methylation, and these genes were prone to transcriptional silencing," the authors report. "These results reveal that epigenetic alleles can arise as a byproduct of maintaining methylation of heterochromatin-associated DNA."

Stanford University researchers report on findings from genomic comparison of Klinefelter syndrome and Turner syndrome — conditions that each involve specific X chromosome copy number changes. Using a combination of RNA sequencing, bisulfite sequencing-based DNA methylation profiling, and chromatin analyses done with Hi-C, the team assessed peripheral blood mononuclear cells from 14 females with Turner syndrome (marked by a missing X chromosome), 14 males with Klinefelter syndrome (which includes an extra X chromosome), and 27 unaffected male and female control individuals. Along with distinct genomic features in the Klinefelter and Turner syndrome cases, the authors uncovered some overlap in the genes that are differentially expressed in the two X chromosome-related conditions. They note that these genes "almost uniformly display expression changes in opposite directions," consistent with a "genome-wide ripple effect of the chromosome X copy number alterations."