Biology subjects

Wei Li

Publications and source records attributed to Wei Li.

4 recordsLinked to original sources

bioRxiv2016

Dual functions of Intraflagellar Transport Protein IFT20 in spermiogenesis: formation of sperm flagella and removal of cytoplasm by autophagy

Intraflagellar transport (IFT) is a conserved mechanism thought to be essential for the assembly and maintenance of cilia and flagella. However, little is known about mammalian sperm flagella formation. To fill this gap, we disrupted the Ift20 gene in male germ cells. Homozygous mutant mice were infertile with significantly reduced sperm counts and motility. In addition, abnormally shaped elongating spermatid heads and bulbous round spermatids were found in the lumen of the seminiferous tubules. Electron microscopy revealed increased cytoplasmic vesicles, fiber-like structures, abnormal accumulation of mitochondria and decreased mature lysosomes. The few developed sperm had disrupted axoneme and retained cytoplasmic lobe components on the flagella. ODF2 and SPAG16L, two sperm flagella proteins failed to be incorporated into sperm tails of the mutant mice. Expression levels of an autophagy core protein that associates with IFT20, Atg16, were significantly reduced in the testis of the Ift20 mutant mice. Our studies suggest that IFT20 is essential for spermiogenesis in mice, and it plays a role in sperm flagella formation, and removing excess cytoplasmic components by regulating autophagy core proteins.

Developmental Biology↗

bioRxiv2015

Global lengthening of 3′ untranslated regions of mRNAs by alternative cleavage and polyadenylation in cellular senescence

Cellular senescence has been viewed as an irreversible cell cycle arrest that acts to prevent cancer. Recent studies discovered widespread shortening of 3' untranslated regions (3' UTRs) by alternative cleavage and polyadenylation (APA) in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. We thus applied our published PA-seq method to investigate APA regulation in different passages of mouse embryonic fibroblasts (MEFs) and aortic vascular smooth muscle cells (VSMCs) from rats of different ages. We found that genes in senescent cells tended to use distal poly(A) sites (pAs). An independent RNA-seq analysis gave rise to the same conclusion. Interestingly, the level of expression of genes preferred to use distal pAs in senescent MFEs and VSMCs tended to decrease. More importantly, genes that preferred to use distal pAs in senescent MFEs and VSMCs were enriched in common senescence-related pathways such as ubiquitin-mediated proteolysis and cell cycle. Further, the longer 3' UTRs of the genes that tended to use distal pAs introduced more conserved binding sites of senescence-related microRNAs (miRNAs) and RNA binding proteins (RBPs). Noteworthy, the expression level of core factors involved in cleavage and the polyadenylation tended to decrease, while those factors showed opposite trend in cancer cells. In summary, we showed, for the first time, that APA is a hidden layer of post-transcriptional gene expression regulation involved in cellular senescence.

Genomics↗

bioRxiv2015

Progressive lengthening of 3′ untranslated regions of mRNAs by alternative cleavage and polyadenylation in cellular senescence of mouse embryonic fibroblasts

BackgroundCellular senescence has historically been viewed as an irreversible cell cycle arrest that acts to prevent cancer. Recent discoveries demonstrated that cellular senescence also played a vital role in normal embryonic development, tissue renewal and senescence-related diseases. Alternative cleavage and polyadenylation (APA) is an important layer of post-transcriptional regulation, which has been found playing an essential role in development, activation of immune cells and cancer progression. However, the role of APA in the process of cellular senescence remains unclear.\n\nMaterials and MethodsWe applied high-throughput paired-end polyadenylation sequencing (PA-seq) and strand-specific RNA-seq sequencing technologies, combined systematic bioinformatics analyses and experimental validation to investigate APA regulation in different passages of mouse embryonic fibroblasts (MEFs) and in aortic vascular smooth muscle cells of rats (VSMCs) with different ages.\n\nResultsBased on PA-seq, we found that genes in senescent cells tended to use distal pA sites and an independent bioinformatics analysis for RNA-seq drew the same conclusion. In consistent with these global results, both the number of genes significantly preferred to use distal pAs in senescent MEFs and VSMCs were significantly higher than genes tended to use proximal pAs. Interestingly, the expression levels of genes preferred to use distal pAs in senescent MFEs and VSMCs tended to decrease, while genes with single pAs did not show such trend. More importantly, genes preferred to use distal pAs in senescent MFEs and VSMCs were both enriched in common senescence-related pathways, including ubiqutin mediated proteolysis, regulation of actin cytoskeleton, cell cycle and wnt signaling pathway. By cis-elements analyses, we found that the longer 3' UTRs of the genes tended to use distal pAs progressively can introduce more conserved binding sites of senescence-related miRNAs and RBPs. Furthermore, 375 genes with progressive 3' UTR lengthening during MEF senescence tended to use more strong and conserved polyadenylation signal (PAS) around distal pA sites and this was accompanied the observation that expression level of core factors involved in cleavage and polyadenylation complex was decreased.\n\nConclusionsOur finding that genes preferred distal pAs in senescent mouse and rat cells provide new insights for aging cells posttranscriptional gene regulation in the view of alternative polyadenylation given senescence response was thought to be a tumor suppression mechanism and more genes tended to use proximal pAs in cancer cells. In short, APA was a hidden layer of post-transcriptional gene expression regulation involved in cellular senescence.

Genomics↗

bioRxiv2015

Exploring functional variation affecting ceRNA regulation in humans

MicroRNA (miRNA) sponges have been shown to function as competing endogenous RNAs (ceRNAs) to regulate the expression of other miRNA targets in the network by sequestering available miRNAs. As the first systematic investigation of the genome-wide genetic effect on ceRNA regulation, we applied multivariate response regression and identified widespread genetic variations that are associated with ceRNA competition using 462 Geuvadis RNA-seq data in multiple human populations. We showed that SNPs in gene 3UTRs at the miRNA seed binding regions can simultaneously regulate gene expression changes in both cis and trans by the ceRNA mechanism. We termed these loci as endogenous miRNA sponge expression quantitative trait loci or \"emsQTLs\", and found that a large number of them were unexplored in conventional eQTL mapping. We identified many emsQTLs are undergoing recent positive selection in different human populations. Using GWAS results, we found that emsQTLs are significantly enriched in traits/diseases associated loci. Functional prediction and prioritization extend our understanding on causality of emsQTL allele in disease pathways. We illustrated that emsQTL can synchronously regulate the expression of tumor suppressor and oncogene through ceRNA competition in angiogenesis. Together these results provide a distinct catalog and characterization of functional noncoding regulatory variants that control ceRNA crosstalk.

Genetics↗