Biology subjects

Gao, Q.

Publications and source records attributed to Gao, Q..

116 records · Page 7Linked to original sources

bioRxiv2019

Splicing factor Rbm10 facilitates heterochromatin assembly in fission yeast

Splicing factors have recently been shown to be involved in heterochromatin formation, but their role in controlling heterochromatin structure and function remains poorly understood. In this study, we identified a fission yeast homologue of human splicing factor RBM10, which has been linked to TARP syndrome. Overexpression of Rbm10 in fission yeast leads to strong global intron retention. Rbm10 also interacts with splicing factors in a pattern resembling that of human RBM10, suggesting that the function of Rbm10 as a splicing regulator is conserved. Surprisingly, our deep-sequencing data showed that deletion of Rbm10 caused only minor effect on genome-wide gene expression and splicing. However, the mutant displays severe heterochromatin defects. Further analyses indicated that the heterochromatin defects in the mutant did not result from mis-splicing of heterochromatin factors. Our proteomic data revealed that Rbm10 associates with the histone deacetylase Clr6 complex and chromatin remodelers known to be important for heterochromatin silencing. Deletion of Rbm10 results in significant reduction of Clr6 in heterochromatin. Our work together with previous findings further suggests that different splicing subunits may play distinct roles in heterochromatin regulation.

molecular biology↗

bioRxiv2018

A new massively parallel nanoball sequencing platform for whole exome research

BackgroundWhole exome sequencing (WES) has been widely used in human genetics research. BGISEQ-500 is a recently established next-generation sequencing platform. However, the performance of BGISEQ-500 on WES is not well studied. In this study, we evaluated the performance of BGISEQ-500 on WES by side-to-side comparison with Hiseq4000, on wellcharacterized human sample NA12878.\n\nResultsBGISEQ demonstrated similarly high reproducibility as Hiseq for variation detection. Also, the SNPs from BGISEQ data is highly consistent with Hiseq results (concordance 96.5%[~]97%). Variation detection accuracy was subsequently evaluated with data from the genome in a bottle project as the benchmark. Both platforms showed similar sensitivity and precision in SNP detection. While in indel detection, BGISEQ showed slightly higher sensitivity and lower precision. The impact of sequence depth and read length on variation detection accuracy was further analyzed, and showed that variation detection sensitivity still increasing when the sequence depth is larger than 100x, and the impact of read length is minor when using 100x data.\n\nConclusionsThis study suggested that BGISEQ-500 is a qualified sequencing platform for WES.

genomics↗

bioRxiv2018

Genome structure and evolution of Antirrhnum majus L.

Snapdragon (Antirrhinum majus L.), a member of Plantaginaceae, is an important model for plant genetics and molecular studies on plant growth and development, transposon biology and self-incompatibility. Here we report a high-quality genome assembly of A. majus cultivated JI7 (A. majus cv.JI7) of a 510 Mb with 37,714 annotated protein-coding genes. The scaffolds covering 97.12% of the assembled genome were anchored on 8 chromosomes. Comparative and evolutionary analyses revealed that Plantaginaceae and Solanaceae diverged from their most recent ancestor around 62 million years ago (MYA). We also revealed the genetic architectures associated with complex traits such as flower asymmetry and self-incompatibility including a unique TCP duplication around 46-49 MYA and a near complete{psi} S-locus of ca.2 Mb. The genome sequence obtained in this study not only provides the first genome sequenced from Plantaginaceae but also bring the popular plant model system of Antirrhinum into a genomic age.

genomics↗

bioRxiv2018

Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation

The different stages of the metastatic cascade present distinct metabolic challenges to tumour cells and an altered tumour metabolism associated with successful metastatic colonisation provides a therapeutic vulnerability in disseminated disease. We identify the aldo-keto reductase AKR1B10 as a metastasis enhancer that has little impact on primary tumour growth or dissemination but promotes effective tumour growth in secondary sites and, in human disease, is associated with an increased risk of distant metastatic relapse. AKR1B10High tumour cells have reduced glycolytic capacity and dependency on glucose as fuel source but increased utilisation of fatty acid oxidation. Conversely, in both 3D tumour spheroid assays and in vivo metastasis assays, inhibition of fatty acid oxidation blocks AKR1B10High-enhanced metastatic colonisation with no impact on AKR1B10Low cells. Finally, mechanistic analysis supports a model in which AKR1B10 serves to limit the toxic side effects of oxidative stress thereby sustaining fatty acid oxidation in metabolically challenging metastatic environments.

cancer biology↗

bioRxiv2018

Core Proteome and Architecture of COPI Vesicles

Retrieval of escaped ER-residents and intra-Golgi transport is facilitated by coat protein complex I (COPI)-coated vesicles. Their formation requires the activated small GTPase ADP-ribosylation factor (Arf) and the coat complex coatomer. Here we assess the protein composition of COPI vesicles by combining stable isotope labeling with amino acids in cell culture (SILAC) with in vitro reconstitution of COPI vesicles from semi-intact cells (SIC) using the minimal set of recombinant coat proteins. This approach yields an unbiased picture of the proteome of these carriers. We define a set of ~40 proteins common to COPI vesicles produced from different human as well as murine cell lines. Almost all bona fide COPI vesicle proteins are either ER-Golgi cycling proteins or Golgi-residents, while only a minor portion of secreted proteins was found. Moreover, we have investigated a putative role of {gamma}- and {zeta}-COP as well as Arf isoforms in sorting and recruitment of specific proteins into COPI vesicles. As opposed to the related COPII system, all isoforms of coatomer and all COPI-forming isoforms of the small GTPase Arf produce COPI-coated vesicles with strikingly similar protein compositions. We present a model for the core architecture of COPI vesicles.

biochemistry↗

bioRxiv2017

Tri-methylation of Histone H3 Lysine 4 Facilitates Gene Expression in Ageing Cells

Transcription of protein coding genes is accompanied by recruitment of COMPASS to promoter-proximal chromatin, which deposits di- and tri-methylation on histone H3 lysine 4 (H3K4) to form H3K4me2 and H3K4me3. Here we determine the importance of COMPASS in maintaining gene expression across lifespan in budding yeast. We find that COMPASS mutations dramatically reduce replicative lifespan and cause widespread gene expression defects. Known repressive functions of H3K4me2 are progressively lost with age, while hundreds of genes become dependent on H3K4me3 for full expression. Induction of these H3K4me3 dependent genes is also impacted in young cells lacking COMPASS components including the H3K4me3-specific factor Spp1. Remarkably, the genome-wide occurrence of H3K4me3 is progressively reduced with age despite widespread transcriptional induction, minimising the normal positive correlation between promoter H3K4me3 and gene expression. Our results provide clear evidence that H3K4me3 is required to attain normal expression levels of many genes across organismal lifespan.

genetics↗

bioRxiv2017

Artemisinin mimics nitric oxide to reduce adipose weight by targeting mitochondrial complexes

It remains obscure how to medically manage visceral obesity that predisposes metabolic disorders. Here, we show for the first time that a trace amount of artemisinin (0.25 mg/kg) reduces adipose weight in an inflammatory obese mouse model induced by a high-fat diet with lipopolysaccharide (HFD+LPS). HFD+LPS trigger pro-inflammatory responses, upregulate NOS2 expression, elicit potent nitric oxide (NO) burst, and reinforce adipose mitochondrial dysfunctions that facilitate adipogenesis for visceral weight gain. By targeting mitochondrial complexes, artemisinin resembles the NO donor nitroglycerin to exert anti-inflammatory effects, downregulate NOS2 expression, maintain stable NO release, and augment adipose mitochondrial functions that necessitate adipolysis for visceral weight loss. Taken together, artemisinin plays adipose weight-reducing roles by rectifying inflammation-driven mitochondrial dysfunctions.

pharmacology and toxicology↗

bioRxiv2017

CD95L mRNA And CD95L Derived si- and shRNAs Kill Cancer Cells Through An RNAi Mechanism By Targeting Survival Genes

Over 80% of multiple tested siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death characterized by simultaneous activation of multiple cell death pathways preferentially killing transformed and cancer stem cells. We now show these si/shRNAs kill cancer cells through canonical RNAi by targeting the 3UTR of critical survival genes in a unique form of off-target effect we call DISE (death induced by survival gene elimination). Drosha and Dicer deficient cells, devoid of most miRNAs, are hypersensitive to DISE, suggesting cellular miRNAs protect cells from this form of cell death. By testing 4666 shRNAs derived from the CD95 and CD95L mRNA sequences and an unrelated control gene, Venus, we have identified many toxic sequences - most of them located in the open reading frame of CD95L. We propose that using specific toxic RNAi-active sequences present in the genome can kill cancer cells.

cancer biology↗