Abstract
Cellular senescence is an important mechanism of autonomous tumor suppression, while its consequence such as the senescence-associated secretory phenotype (SASP) may drive tumorigenesis and age-related diseases. Therefore, controlling the cell fate optimally when encountering senescence stress is helpful for anti-cancer or anti-aging treatments. To identify genes essential for senescence establishment or maintenance, we carried out a CRISPR-based screen with a deliberately designed single-guide RNA (sgRNA) library. The library comprised of about 12,000 kinds of sgRNAs targeting 1378 senescence-associated genes selected by integrating the information of literature mining, protein-protein interaction network, and differential gene expression. We successfully detected a dozen gene deficiencies potentially causing senescence bypass, and their phenotypes were further validated with a high true positive rate. RNA-seq analysis showed distinct transcriptome patterns of these bypass cells. Interestingly, in the bypass cells, the expression of SASP genes was maintained or elevated with CHEK2, HAS1, or MDK deficiency; but neutralized with MTOR, CRISPLD2, or MORF4L1 deficiency. Pathways of some age-related neurodegenerative disorders were also downregulated with MTOR, CRISPLD2, or MORF4L1 deficiency. The results demonstrated that disturbing these genes could lead to distinct cell fates as a consequence of senescence bypass, suggesting that they may play essential roles in cellular senescence.
Highlights
Pulmonary arterial hypertension (PAH) is pathologically featured by the narrowing and obliteration of small pulmonary arteries [1]
transient receptor potential melastatin 7 (TRPM7) has been implicated in vascular pathological changes that underlie hypertension [18, 23], whether it is associated with pulmonary arterial hypertension (PAH) pathogenesis remains unknown
We initially examined its expression in pulmonary artery smooth muscle cells (PASMCs) obtained from PAH patients and control donors. qRT-PCR analysis showed that compared with PASMCs from control donors, the mRNA level of TRPM7 was significantly downregulated in PASMCs from PAH patients (Figure 1A)
Summary
Pulmonary arterial hypertension (PAH) is pathologically featured by the narrowing and obliteration of small pulmonary arteries [1]. During the pathogenesis of PAH, the increased proliferation and apoptosis resistance of endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts accelerate the remodeling of pulmonary arteries [6]. The physiological abnormalities, including the upregulation of growth factors and metabolic changes, render the vascular wall of pulmonary arteries a pro-proliferative and anti-apoptotic microenvironment in PAH patients [7,8,9]. It might be unsurprising that anti-neoplastic drugs capable of inhibiting proliferation and reversing apoptosis resistance show beneficial effects in PAH treatment [10, 11]. We hypothesized that proteins www.aging-us.com involved in the regulation of proliferation and apoptosis of pulmonary artery cells may influence PAH pathogenesis and that their targeting might provide a new option for PAH therapy
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