RNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline. We identify the full-length coding transcripts of CACNA1C in human brain. CACNA1C is a psychiatric risk gene that encodes the voltage-gated calcium channel Ca V 1.2. We show that CACNA1C's transcript profile is substantially more complex than appreciated, identifying 38 novel exons and 241 novel transcripts. Importantly, many of the novel variants are abundant, and predicted to encode channels with altered function. The splicing profile varies between brain regions, especially in cerebellum. We demonstrate that human transcript diversity (and thereby protein isoform diversity) remains undercharacterised, and provide a feasible and cost-effective methodology to address this. A detailed understanding of isoform diversity will be essential for the translation of psychiatric genomic findings into pathophysiological insights and novel psychopharmacological targets.
Senescence is a ubiquitous characteristic in the biological world. From an ontogenetic perspective, senescence is now established as a developmental and genetic program acquired during evolution (Wojciechowska et al., 2018). Like in other organisms, senescence in plants is genetically programmed (Nam, 1997; van Doorn and Woltering, 2004; Wojciechowska et al., 2018). In plants, senescence is a prelude to cell (organ) death, and during this process metabolites and macromolecules released are salvaged for utilization by the plant for growth. Generally, senescence occurs prior to programmed cell death (PCD), since symptomatic leaf yellowing can be reversed based on the timing of senescence while PCD is a terminal, irreversible program. It has been suggested that the term "PCD" in plants should be restricted to the specific stage of intrinsic senescence program when it has reached a "point of no return" and leaf yellowing is no longer reversible (Mattoo and Handa, 2003). Programmed cell death in plants was described as a sequential process that included apoptosis-like necrosis and autophagy (van Doorn et al., 2011). Autophagy under normal growth conditions favors turnover of cellular components for maintaining homeostasis,
BackgroundVHL inactivation is the most established molecular characteristic of clear cell renal cell carcinoma (ccRCC), with only a few additional genes implicated in development of this kidney tumor. In recently published ccRCC gene expression meta-analysis study we identified a number of deregulated genes with limited information available concerning their biological role, represented by gene transcripts belonging to transmembrane proteins family (TMEMs). TMEMs are predicted to be components of cellular membranes, such as mitochondrial membranes, ER, lysosomes and Golgi apparatus. Interestingly, the function of majority of TMEMs remains unclear. Here, we analyzed expression of ten TMEM genes in the context of ccRCC progression and development, and characterized these proteins bioinformatically.MethodsThe expression of ten TMEMs (RTP3, SLC35G2, TMEM30B, TMEM45A, TMEM45B, TMEM61, TMEM72, TMEM116, TMEM207 and TMEM213) was measured by qPCR. T-test, Pearson correlation, univariate and multivariate logistic and Cox regression were used in statistical analysis. The topology of studied proteins was predicted with Metaserver, together with PSORTII, Pfam and Localizome tools.ResultsWe observed significant deregulation of expression of 10 analyzed TMEMs in ccRCC tumors. Cluster analysis of expression data suggested the down-regulation of all tested TMEMs to be a descriptor of the most advanced tumors. Logistic and Cox regression potentially linked TMEM expression to clinical parameters such as: metastasis, Fuhrman grade and overall survival. Topology predictions classified majority of analyzed TMEMs as type 3 and type 1 transmembrane proteins, with predicted localization mainly in ER.ConclusionsThe massive down-regulation of expression of TMEM family members suggests their importance in the pathogenesis of ccRCC and the bioinformatic analysis of TMEM topology implies a significant involvement of ER proteins in ccRCC pathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1530-4) contains supplementary material, which is available to authorized users.
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