Splicing regulatory factors, ageing and age-related disease

Latorre, Eva; Harries, Lorna W.

doi:10.1016/j.arr.2017.04.004

Cited by 48 publications

(39 citation statements)

References 102 publications

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“…Ageing presents numerous progressive changes in molecular, cellular, tissular and organismal functions, which ultimately drives various diseases and limits lifespan [ 1 ]. Consequently, age has been confirmed to be the strongest demographic risk factor for most common chronic human diseases, including cancers [ 2 ]. Ageing indicates accumulation of somatic mutations as well as aberrant epigenetic changes (epimutations) [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Decelerated DNA methylation age predicts poor prognosis of breast cancer

Ren¹,

Wang²,

Su³

et al. 2018

BMC Cancer

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BackgroundDNA methylation (DNAm) age was found to be an indicator for all-cause mortality, cancer incidence, and longevity, but no study has involved in the associations of DNAm age with the prognosis of breast cancer.MethodsWe retrieved information of 1076 breast cancer patients from Genomic Data Commons (GDC) data portal on March 30, 2017, including breast cancer DNAm profiling, demographic features, clinicopathological parameters, recurrence, and all-cause fatality. Horvath’s method was applied to calculate the DNAm age. Cox proportional hazards regression models were used to test the associations between DNAm age of the cancerous tissues and the prognosis (recurrence of breast cancer and all-cause fatality) with or without adjusting for chronological age and clinicopathological parameters.ResultsThe DNAm age was markedly decelerated in the patients who were premenopausal, ER or PR negative, HER2-enriched or basal-like than their counterparts. In the first five-year follow-up dataset for survival, every ten-year increase in DNAm age was associated with a 15% decrease in fatality; subjects with DNAm age in the second (HR: 0.52; 95%CI: 0.29–0.92), the third (HR: 0.49; 95%CI: 0.27–0.87) and the fourth quartile (HR: 0.38; 95%CI: 0.20–0.72) had significant longer survival time than those in the first quartile. In the first five-year follow-up dataset for recurrence, every ten-year increase in DNAm age was associated with a 14% decrease of the recurrence; in the categorical analysis, a clear dose-response was shown (P for trend =0.02) and the fourth quartile was associated with a longer recurrence free survival (HR: 0.32; 95%CI: 0.14–0.74). In the full follow-up dataset, similar results were obtained.ConclusionsDNAm age of breast cancer tissue, which associated with menopausal status and pathological features, was a strong independent predictor of the prognosis. It was suggested that the prognosis of breast cancer was related to intrinsic biological changes and specific molecular targets for treatment of breast cancer may be implicit.

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Section: Introductionmentioning

confidence: 99%

Decelerated DNA methylation age predicts poor prognosis of breast cancer

Ren¹,

Wang²,

Su³

et al. 2018

BMC Cancer

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“…As alternative mRNA splicing is tightly regulated by signaling pathway to cope with the physiological changes [ 23 ], diet-induced obesity model can be applied in the investigations of the significance of alternative mRNA splicing in the pathogenesis of obesity. Indeed, significant changes in the expression level of splice variants and splicing factors in association with age and metabolic dysregulation in animal models, as well as in human populations, had already been reported [ 25 , 26 , 27 , 28 , 29 , 30 ]. Dysregulation of alternative mRNA splicing may stipulate an important driver of ageing process and metabolic diseases.…”

Section: Introductionmentioning

confidence: 99%

Alternative mRNA Splicing in the Pathogenesis of Obesity

Wong

Yau

2018

IJMS

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Alternative mRNA splicing is an important mechanism in expansion of proteome diversity by production of multiple protein isoforms. However, emerging evidence indicates that only a limited number of annotated protein isoforms by alternative splicing are detected, and the coding sequence of alternative splice variants usually is only slightly different from that of the canonical sequence. Nevertheless, mis-splicing is associated with a large array of human diseases. Previous reviews mainly focused on hereditary and somatic mutations in cis-acting RNA sequence elements and trans-acting splicing factors. The importance of environmental perturbations contributed to mis-splicing is not assessed. As significant changes in exon skipping and splicing factors expression levels are observed with diet-induced obesity, this review focuses on several well-known alternatively spliced metabolic factors and discusses recent advances in the regulation of the expressions of splice variants under the pathophysiological conditions of obesity. The potential of targeting the alternative mRNA mis-splicing for obesity-associated diseases therapies will also be discussed.

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“…A systematic change in the splicing machinery with older age was previously suggested by transcriptomic analyses skeletal muscle biopsies 51 and human peripheral blood leukocytes 52 of young and old individuals. In both studies, processing of mRNAs was the feature that best discriminated younger and older persons, suggesting that modulation of alternative splicing is one of the signatures of aging 53 . Although the mechanisms and consequences of the rise in splicing factors with aging are unknown, they may indicate either a dysregulation of the splicing apparatus or a shift toward increased splicing and/or altered splice isoform diversity with aging 54 .…”

Section: Implications Of Proteins That Modulate Transcription and Splmentioning

confidence: 89%

Aging Skeletal Muscle Proteomics Finds Changes in Spliceosome, Immune factors, Proteostasis and Mitochondria

Ubaida‐Mohien

Lyashkov

González-Freire

et al. 2019

Preprint

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A progressive decline of skeletal muscle strength with aging is a primary cause of mobility loss and frailty in older persons, but the molecular mechanisms of such decline are not fully understood. Here, using quantitative discovery proteomic data from skeletal muscle specimens collected from 58 healthy persons aged 20 to 87 years show that ribosomal proteins and proteins related to energetic metabolism, including those related to the TCA cycle, mitochondria respiration, and glycolysis were underrepresented in older persons.Proteins with important roles in innate and adaptive immunity, involved in proteostasis and regulation of alternative splicing were all overrepresented in muscle from older persons.Changes with aging of alternative splicing were confirmed by RNA-seq. Overall, older muscle has a profound deficit of energetic metabolism, a pro-inflammatory environment and increased proteostasis. Upregulation of the splicing machinery maybe an attempt to compensate for these changes and this could be tested in future studies. 20 30 40 50 60 70 80 −0.4 0.0 0.2 0.4 r 2 = 0.05, p = 0.13872 Figure 7Supplemental Information Aging Skeletal Muscle Proteomics Finds Changes in Spliceosome, Immune factors, Proteostasis and Mitochondria

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Splicing regulatory factors, ageing and age-related disease

Cited by 48 publications

References 102 publications

Decelerated DNA methylation age predicts poor prognosis of breast cancer

Decelerated DNA methylation age predicts poor prognosis of breast cancer

Alternative mRNA Splicing in the Pathogenesis of Obesity

Aging Skeletal Muscle Proteomics Finds Changes in Spliceosome, Immune factors, Proteostasis and Mitochondria

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