Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and RNA polymerase II chromatin immunoprecipitation followed by sequencing to elucidate the underlying mechanisms triggering gene expression changes in wild-type aged mice. We found that in 2-year-old liver, 40% of elongating RNA polymerases are stalled, lowering productive transcription and skewing transcriptional output in a gene-length-dependent fashion. We demonstrate that this transcriptional stress is caused by endogenous DNA damage and explains the majority of gene expression changes in aging in most mainly postmitotic organs, specifically affecting aging hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function and cellular stress resilience. Age-related transcriptional stress is evolutionary conserved from nematodes to humans. Thus, accumulation of stochastic endogenous DNA damage during aging deteriorates basal transcription, which establishes the age-related transcriptome and causes dysfunction of key aging hallmark pathways, disclosing how DNA damage functionally underlies major aspects of normal aging.

Uveal melanoma (UM) is the most frequently found primary intra-ocular tumor in adults. It is a highly aggressive cancer that causes metastasis-related mortality in up to half of the patients. Many independent studies have reported somatic genetic changes associated with high metastatic risk, such as monosomy of chromosome 3 and mutations in BAP1. Still, the mechanisms that drive metastatic spread are largely unknown. This study aimed to elucidate the potential role of microRNAs in the metastasis of UM. Using a next-generation sequencing approach in 26 UM samples we identified thirteen differentially expressed microRNAs between high-risk UM and low/intermediate-risk UM, including the known oncomirs microRNA-17-5p, microRNA-21-5p, and miR-151a-3p. Integration of the differentially expressed microRNAs with expression data of predicted target genes revealed 106 genes likely to be affected by aberrant microRNA expression. These genes were involved in pathways such as cell cycle regulation, EGF signaling and EIF2 signaling. Our findings demonstrate that aberrant microRNA expression in UM may affect the expression of genes in a variety of cancer-related pathways. This implies that some microRNAs can be responsible for UM metastasis and are promising potential targets for future treatment.

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To identify genetic risk factors underlying non-Hodgkin lymphomas (NHLs) from the B cell lineage, we conducted a genome-wide association study (GWAS) of 253 Chinese individuals with B cell NHL (cases) and 1,438 controls and further validation in 1,175 cases and 5,492 controls. We identified a new susceptibility locus, rs6773854, located between BCL6 (encoding B cell lymphoma protein 6) and LPP (encoding lipoma preferred partner) on oncogene-rich chromosome 3q27 that was significantly associated with increased risk of B cell NHL (meta-analysis P = 3.36 × 10⁻¹³, per-allele odds ratio (OR) = 1.44) and with diffuse large B cell lymphoma (DLBCL) in particular (meta-analysis P = 1.14 × 10⁻¹¹, OR = 1.47). We found no evidence of association of rs6773854 with non-B cell NHLs (T cell and natural killer (NK) lineages) (P = 0.17, OR = 1.12) and observed significant heterogeneity between B cell and non-B cell subtypes (Phet = 0.01, I² = 84%). Our results provide insight that germline variation in the intergenic region between BCL6 and LPP has a role in risk of B cell lymphomagenesis.