Biology subjects

Zhou, M.

Publications and source records attributed to Zhou, M..

9 recordsLinked to original sources

bioRxiv2018

ROCK1/Drp1-mediated aberrant mitochondrial fission is crucial for dopaminergic nerve cell apoptosis

Dopamine deficiency caused by apoptosis of the dopaminergic nerve cells in the midbrain substantia nigra is the main pathological basis of Parkinson's disease (PD). Recent research has shown that dynamin-related protein 1 (Drp1)-mediated aberrant mitochondrial fission plays an important role in dopaminergic nerve cell apoptosis. However, the upstream regulatory mechanism remains unclear. Our study shows that knockdown of Drp1 blocked aberrant mitochondrial fission and dopaminergic nerve cell apoptosis. Importantly, we found that ROCK1 was activated in an MPP+-induced PD cell model and that ROCK1 knockdown and the specific ROCK1 activation inhibitor Y-27632 blocked Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic nerve cell through suppression of Drp1 dephosphorylation/activation. Our in vivo study confirmed that Y-27632 significantly improved symptoms of a PD mouse model through inhibition of Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic nerve cell. Collectively, Our study suggests an important molecular mechanism of PD pathogenesis involving ROCK1-regulated dopaminergic nerve cell apoptosis via activation of Drp1-induced aberrant mitochondrial fission.

neuroscience↗

bioRxiv2018

Hybridization and postzygotic isolation promote reinforcement of male mating preferences in a diverse group of fishes with traditional sex roles

Behavioral isolation is thought to arise early in speciation due to differential sexual and/or natural selection favoring different preferences and traits in different lineages. Alternatively, behavioral isolation can arise due to reinforcement favoring traits and preferences that prevent maladaptive hybridization. In darters, female preference for male coloration has been hypothesized to drive speciation, because behavioral isolation evolves before F1 inviability. However, as with many long-lived organisms, the fitness of second generation hybrids has not been assessed because raising animals to adulthood in the lab is challenging. Recently, reinforcement of male preferences has been implicated in darters because male preference for conspecific females is high in sympatry but absent in allopatry in multiple species pairs. The hypothesis that reinforcement accounts for behavioral isolation in sympatry assumes that hybridization and postzygotic isolation are present. Here, we used genomic and morphological data to demonstrate that hybridization is ongoing between orangethroat and rainbow darters and used hybrids collected from nature to measure postzygotic barriers across two hybrid generations. We observed sex ratio distortion in adult F1s and a dramatic reduction in backcross survival. Our findings indicate that selection to avoid hybridization promotes the evolution of male-driven behavioral isolation via reinforcement in this system.

evolutionary biology↗

bioRxiv2018

Expression levels of glycoprotein O (gO) vary between strains of human cytomegalovirus, influencing the assembly of gH/gL complexes and virion infectivity.

Tropism of human cytomegalovirus (HCMV) is influenced by the envelope glycoprotein complexes gH/gL/gO and gH/gL/UL128-131. During virion assembly, gO and the UL128-131 proteins compete for binding to gH/gL in the ER. This assembly process clearly differs among strains since Merlin (ME) virions contain abundant gH/gL/UL128-131 and little gH/gL/gO, whereas TR contains much higher levels of total gH/gL, mostly in the form of gH/gL/gO, but much less gH/gL/UL128-131 than ME. Remaining questions include 1) what are the mechanisms behind these assembly differences, and 2) do differences reflect in vitro culture adaptations or natural genetic variations? Since the UL74(gO) ORF differs by 25% of amino acids between TR and ME, we analyzed recombinant viruses in which the UL74(gO) ORF was swapped. TR virions were >40-fold more infectious than ME. Transcriptional repression of UL128-131 enhanced infectivity of ME to the level of TR, despite still far lower levels of gH/gL/gO. Swapping the UL74(gO) ORF had no effect on either TR or ME. A quantitative immunoprecipitation approach revealed that gH/gL expression was within 4-fold between TR and ME, but gO expression was 20-fold less by ME, and suggested differences in mRNA transcription, translation or rapid ER-associated degradation of gO. Trans-complementation of gO expression during ME replication gave 6-fold enhancement of infectivity beyond the 40-fold effect of UL128-131 repression alone. Overall, strain variations in assembly of gH/gL complexes result from differences in expression of gO and UL128-131, and selective advantages for reduced UL128-131 expression during fibroblast propagation are much stronger than for higher gO expression.\n\nIMPORTANCESpecific genetic differences between independently isolated HCMV strains may result from purifying selection on de novo mutations arising during propagation in culture, or random sampling among the diversity of genotypes present in clinical specimens. Results presented indicate that while reduced UL128-131 expression may confer a powerful selective advantage during cell-free propagation of HCMV in fibroblast cultures, selective pressures for increased gO expression are much weaker. Thus, variation in gO expression among independent strains may represent natural genotype variability present in vivo. This may have important implications for virus-host interactions such as immune recognition, and underscores the value of studying molecular mechanisms of replication using multiple HCMV strains.

microbiology↗

bioRxiv2018

Crystal structure of chromo barrel domain of RBBP1

RBBP1 is a retinoblastoma protein (pRb) binding protein acting as a repressor of gene transcription. RBBP1 is a multidomain protein including a chromo barrel domain, and its chromo barrel domain has been reported to recognize histone H4K20me3 weakly, and this binding is enhanced by the simultaneous binding of DNA. However, the molecular basis of this DNA-mediated histone binding by the chromo barrel domain of RBBP1 is unclear. Here we attempted to co-crystallize the chromo barrel domain of RBBP1 with either a histone H4K20me3 peptide alone or with both a histone H4K20me3 peptide and DNA, but only solved the peptide/DNA unbound crystal structure. Our structural analysis indicates that RBBP1 could interact with histone H4K20me3 similar to other histone binding chromo barrel domains, and the surface charge representation analysis of the chromo barrel domain of RBBP1 suggests that the chromo barrel domain of RBBP1 does not have a typical DNA binding surface, indicating that it might not bind to DNA. Consistently, our ITC assays also showed that DNA does not significantly enhance the histone binding ability of the chromo barrel domain of RBBP1.

biochemistry↗

bioRxiv2017

Boosting ATM Activity Promotes Longevity in Nematodes and Mice

DNA damage accumulates with age1. However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that activation of ataxia-telangiectasia mutated (ATM) via low dose of chloroquine (CQ) promotes DNA damage clearance, rescues age-related metabolic shift, and extends lifespan in nematodes and mice. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 in Atm-/- mice extend lifespan, accompanied with restored metabolic homeostasis. In a progeria mouse model with low ATM protein level and DNA repair capacity, the treatment with CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases.

molecular biology↗

bioRxiv2017

BayCount: A Bayesian Decomposition Method for Inferring Tumor Heterogeneity using RNA-Seq Counts

Tumors are heterogeneous - a tumor sample usually consists of a set of subclones with distinct transcriptional profiles and potentially different degrees of aggressiveness and responses to drugs. Understanding tumor heterogeneity is therefore critical for precise cancer prognosis and treatment. In this paper, we introduce BayCount, a Bayesian decomposition method to infer tumor heterogeneity with highly over-dispersed RNA sequencing count data. Using negative binomial factor analysis, BayCount takes into account both the between-sample and gene-specific random effects on raw counts of sequencing reads mapped to each gene. For the posterior inference, we develop an efficient compound Poisson based blocked Gibbs sampler. Simulation studies show that BayCount is able to accurately estimate the subclonal inference, including number of subclones, the proportions of these subclones in each tumor sample, and the gene expression profiles in each subclone. For real-world data examples, we apply BayCount to The Cancer Genome Atlas lung cancer and kidney cancer RNA sequencing count data and obtain biologically interpretable results. Our method represents the first effort in characterizing tumor heterogeneity using RNA sequencing count data that simultaneously removes the need of normalizing the counts, achieves statistical robustness, and obtains biologically/clinically meaningful insights. The R package BayCount implementing our model and algorithm is available for download.

bioinformatics↗

bioRxiv2017

Egg viability decreases rapidly with time since ovulation in the rainbow darter: implications for the costs of choosiness

Egg viability in the rainbow darter Etheostoma caeruleum, a fish apparently lacking female mate choice, was found to decline rapidly after ovulation. We observed that the majority of a females clutch may fail to hatch if she is prevented from mating for as little as six hours. These data suggest that exercising female mate preferences may be selectively disfavoured in E. caeruleum due to the high cost of delaying mating.

animal behavior and cognition↗

bioRxiv2017

The rumen microbiome: an underexplored resource for novel antimicrobial discovery

Antimicrobial peptides (AMPs) are promising drug candidates to target multi-drug resistant bacteria. The rumen microbiome presents an underexplored resource for the discovery of novel microbial enzymes and metabolites, including AMPs. Using functional screening and computational approaches, we identified 181 potentially novel AMPs from a rumen bacterial metagenome. Here, we show that three of the selected AMPs (Lynronne-1, 2 and 3) were effective against numerous bacterial pathogens, including methicillin resistant Staphylococcus aureus (MRSA). No decrease in MRSA susceptibility was observed after 25 days of sub-lethal exposure to these AMPs. The AMPs bound preferentially to bacterial membrane lipids and induced membrane permeability leading to cytoplasmic leakage. Topical administration of Lynronne-1 (10% w/v) to a mouse model of MRSA wound infection elicited a significant reduction in bacterial counts, which was comparable to treatment with 2% mupirocin ointment. Our findings indicate that the rumen microbiome may provide viable alternative antimicrobials for future therapeutic application.

microbiology↗

bioRxiv2017

LncRNA-TUG1/EZH2 Axis Promotes Cell Proliferation, Migration And The EMT Phenotype Formation Through Sponging miR-382

Pancreatic carcinoma (PC) is the one of the most common and malignant cancer in the world. Despite many effort have been made in recent years, the survival rate of PC still remains unsatisfied. Therefore, investigating the mechanisms underlying the progression of PC might facilitate the development of novel treatments that improve patient prognosis. LncRNA Taurine Up-regulated Gene 1 (TUG1) was initially identified as a transcript up - regulated by taurine, siRNA - based depletion of TUG1 suppresses mouse retinal development, and the abnormal expression of TUG1 has been reported in many cancers. However, the biological role and molecular mechanism of TUG1 in pancreatic carcinoma (PC) still needs to be further investigated. In the current study, the expression of TUG1 in the PC cell lines and tissues was measured by quantitative real-time PCR (qRT-PCR), and loss-of-function and gain-of-function approaches were applied to investigate the function of TUG1 in PC cell. Online database analysis tools showed that miR-382 could interact with TUG1 and we found an inverse correlation between TUG1 and miR-382 in PC specimens. Moreover, dual luciferase reporter assay, RNA-binding protein immunoprecipitation (RIP) and applied biotin-avidin pulldown system further provide evidence that TUG1 directly targeted miR-382 by binding with microRNA binding site harboring in the TUG1 sequence. Furthermore, gene expression array analysis using clinical samples and RT-qPCR proposed that EZH2 was a target of miR-382 in PC. Collectively, these findings revealed that TUG1 functions as an oncogenic lncRNA that promotes tumor progression at least partially through function as an endogenous sponge by competing for miR-382 binding to regulate the miRNA target EZH2.

cancer biology↗