Abstract Age is a major risk factor for lung disease. Accumulation of somatic mutations has been implicated in both aging and cellular senescence. We analyzed somatic mutations called from single-cell RNAseq (scRNAseq) data. scRNAseq was performed on lung parenchyma samples from healthy donors (32 samples, 11-72 years, 21M/11F). Following standard pre-processing and cell type annotation, mutations were called using SComatic with the default parameters. Mutation burden was calculated for each cell type-sample combination by dividing the number of mutations by the number of callable sites. Our resulting scRNAseq dataset consisted of 199,400 cells, comprising 25 distinct cell types. Mutation burden was highest in alveolar type 1 (AT1) cells (93.6 mutations/MB), alveolar macrophages (79.1), and general capillary (gCap) cells (62.1). Mutation burden was positively correlated with age (r=0.28, p< 0.001). Globally, the top genes correlated with mutation burden included ubiquitin ligase genes (AMBRA1, ANAPC1, SEL1L, USP25, USP33) and DNA damage response genes (RAD50, PRKDC). Notably, mutation burden also correlated with expression of senescence marker CDKN2A (r=0.48, p< 0.05). In AT1 cells, mutation burden correlated with decreased expression of cell marker genes such as AGER (r=-0.64, p< 0.05) and HOPX (r=-0.83, p< 0.05). Similarly, gCap cells exhibited decreased expression of marker genes Il7R (r=-0.54) and VIPR1 (r=-0.64), while MAPK/ERK signaling genes were increased (p < 0.05). These genes were also significantly correlated with age in the same direction (p < 0.05). These results suggest that somatic mutation accumulation may contribute to age-associated transcriptional changes and loss of cell function, with cell types of the alveoli and endothelium experiencing the greatest effects.

Supplementary Figure Legends 1-2, Methods from SLC45A3-ELK4 Is a Novel and Frequent Erythroblast Transformation–Specific Fusion Transcript in Prostate Cancer

Supplementary Figure 1 from SLC45A3-ELK4 Is a Novel and Frequent Erythroblast Transformation–Specific Fusion Transcript in Prostate Cancer

Supplementary Figure 2 from SLC45A3-ELK4 Is a Novel and Frequent Erythroblast Transformation–Specific Fusion Transcript in Prostate Cancer

"Defining the Genetic Landscape of IPF: Role of Common and Rare Variants ." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –

The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves a complex interplay of cell types and signaling pathways. Recurrent alveolar epithelial cell (AEC) injury may occur in the context of predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, and gerontologic), leading to metabolic dysfunction, senescence, aberrant epithelial cell activation, and dysregulated epithelial repair. The dysregulated epithelial cell interacts with mesenchymal, immune, and endothelial cells via multiple signaling mechanisms to trigger fibroblast and myofibroblast activation. Recent single-cell RNA sequencing studies of IPF lungs support the epithelial injury model. These studies have uncovered a novel type of AEC with characteristics of an aberrant basal cell, which may disrupt normal epithelial repair and propagate a profibrotic phenotype. Here, we review the pathogenesis of IPF in the context of novel bioinformatics tools as strategies to discover pathways of disease, cell-specific mechanisms, and cell-cell interactions that propagate the profibrotic niche.

Critical Care Medicine: January 2020 - Volume 48 - Issue 1 - p 677 doi: 10.1097/01.ccm.0000645520.77275.1f

[This corrects the article DOI: 10.1093/ofid/ofaa307.].