Insights into the Coupling of Duplication Events and Macroevolution from an Age Profile of Animal Transmembrane Gene Families

The evolution of new gene families subsequent to gene duplication may be coupled to the fluctuation of population and environment variables. Based upon that, we presented a systematic analysis of the animal transmembrane gene duplication events on a macroevolutionary scale by integrating the palaeontology repository. The age of duplication events was calculated by maximum likelihood method, and the age distribution was estimated by density histogram and normal kernel density estimation. We showed that the density of the duplicates displays a positive correlation with the estimates of maximum number of cell types of common ancestors, and the oxidation events played a key role in the major transitions of this density trace. Next, we focused on the Phanerozoic phase, during which more macroevolution data are available. The pulse mass extinction timepoints coincide with the local peaks of the age distribution, suggesting that the transmembrane gene duplicates fixed frequently when the environment changed dramatically. Moreover, a 61-million-year cycle is the most possible cycle in this phase by spectral analysis, which is consistent with the cycles recently detected in biodiversity. Our data thus elucidate a strong coupling of duplication events and macroevolution; furthermore, our method also provides a new way to address these questions

MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis

MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis Changsheng Du1,5, Chang Liu1,5, Jiuhong Kang1,2, Guixian Zhao3, Zhiqiang Ye4, Shichao Huang1, Zhenxin Li3, Zhiying Wu3 & Gang Pei1,2 Interleukin 17 (IL-17)-producing T helper cells (TH-17 cells) are increasingly recognized as key participants in various autoimmune diseases, including multiple sclerosis. Although sets of transcription factors and cytokines are known to regulate TH-17 differentiation, the role of noncoding RNA is poorly understood. Here we identify a TH-17 cell–associated microRNA, miR-326, whose expression was highly correlated with disease severity in patients with multiple sclerosis and mice with experimental autoimmune encephalomyelitis (EAE). In vivo silencing of miR-326 resulted in fewer TH-17 cells and mild EAE, and its overexpression led to more TH-17 cells and severe EAE. We also found that miR-326 promoted TH-17 differentiation by targeting Ets-1, a negative regulator of TH-17 differentiation. Our data show a critical role for microRNA in TH-17 differentiation and the pathogenesis of multiple sclerosis

Improvement of Morphine-Mediated Analgesia by Inhibition of β-Arrestin 2 Expression in Mice Periaqueductal Gray Matter

Morphine is a well-known μ-opioid receptor (MOR) agonist and an efficient analgesic, but its long-term use inevitably leads to drug addiction and tolerance. Here, we show that specific inhibition of β-arrestin2 with its siRNA lentivirus microinjected in mice periaqueductal gray matter (PAG) significantly improved both acute and chronic morphine analgesia and delayed the tolerance in the hotplate test. The specific effect of β-arrestin2 was proven by overexpression or knockdown of its homology β-arrestin1 in PAG, which showed no significant effects on morphine analgesia. These findings suggest that specific siRNA targeting β-arrestin2 may constitute a new approach to morphine therapy and other MOR agonist-mediated analgesia and tolerance

A single amino acid substitution confers enhanced methylation activity of mammalian Dnmt3b on chromatin DNA

Dnmt3a and Dnmt3b are paralogous enzymes responsible for de novo DNA methylation but with distinguished biological functions. In mice, disruption of Dnmt3b but not Dnmt3a causes global DNA hypomethylation, especially in repetitive sequences, which comprise the large majority of methylated DNA in the genome. By measuring DNA methylation activity of Dnmt3a and Dnmt3b homologues from five species, we found that mammalian Dnmt3b possessed significantly higher methylation activity on chromatin DNA than Dnmt3a and non-mammalian Dnmt3b. Sequence comparison and mutagenesis experiments identified a single amino acid substitution (I662N) in mammalian Dnmt3b as being crucial for its high chromatin DNA methylation activity. Further mechanistic studies demonstrated this substitution markedly enhanced the binding of Dnmt3b to nucleosomes and hence increased the chromatin DNA methylation activity. Moreover, this substitution was crucial for Dnmt3b to efficiently methylate repetitive sequences, which increased dramatically in mammalian genomes. Consistent with our observation that Dnmt3b evolved more rapidly than Dnmt3a during the emergence of mammals, these results demonstrated that the I662N substitution in mammalian Dnmt3b conferred enhanced chromatin DNA methylation activity and contributed to functional adaptation in the epigenetic system

Contribution of the -160C/A polymorphism in the E-cadherin promoter to cancer risk: a meta-analysis of 47 case-control studies.

BACKGROUND: The -160C/A polymorphism (rs16260) of E-cadherin, a tumor repressor gene, has been shown to be a tumor susceptibility allele for various types of cancers. Because the significance of this polymorphism to cancer risk has been recognized, there are increasing studies investigating -160C/A in different types of cancers and ethnic populations. However, there is still uncertainty about the level of risk for a variety of cancers. METHODS: To resolve the controversial question raised by these studies as of March 2012 and provide more statistical power for detecting the significance of -160C/A, we performed a meta-analysis of 47 case-control studies in 16 types of cancers (18,194 cases and 20,207 controls). A meta-regression model and subgroup analysis were employed to identify the source of heterogeneity. Publication bias was evaluated, and sensitivity analysis and cumulative evidence assessment were also performed. RESULTS: Using fixed- and random-effects models, the -160AA homozygote was more susceptible to urothelial cancer compared with the -160CA heterozygote. Additionally, the -160A allele is an ethnicity-dependent risk factor for prostate and colorectal cancers. Carriers of the -160A allele in Asians and Europeans were more susceptible to prostate cancer, whereas their North American counterparts seemed tolerant. The -160AA homozygote plays a protective role for Europeans who develop colorectal cancer. The stability of these observations was confirmed by a one-way sensitivity analysis. However, the cumulative evidence for all cancer types was considered 'weak' using the Venice guidelines. CONCLUSIONS: A meta-analysis indicated that the -160A allele of E-cadherin provides a higher risk for the development of prostate and urothelial cancers and a protective role for colorectal cancer in an ethnicity-dependent manner

NRG1 knockdown rescues PV interneuron GABAergic maturation deficits and schizophrenia behaviors in fetal growth restriction mice

Abstract Schizophrenia is a highly debilitating mental disorder, those who experienced fetal growth restriction (FGR) in the early stage of life have a greater probability of schizophrenia. In this study, FGR mice showed hyperactivity in locomotor activity test, sociability dysfunction in three chamber test and nesting social behavior tests, cognition decline in Morris water maze and impaired sensory motor gating function in prepulse inhibition test. Mechanistic studies indicated that the number of parvalbumin (PV) interneuron was significantly reduced in FGR mouse media prefrontal cortex (mPFC). And the mRNA and protein level of neuregulin 1(NRG1), which is a critical schizophrenia gene, increased significantly in FGR mouse mPFC. Furthermore, NRG1 knockdown in FGR mouse mPFC improved PV interneuron GABAergic maturation and rescued schizophrenia behaviors including hyperactivity, social novelty defects, cognition decline, and sensorimotor gating deficits in FGR mice. This study indicates that mPFC NRG1 upregulation is one of the main causes of FGR-induced schizophrenia, which leads to significant reduction of PV interneuron number in mPFC. NRG1 knockdown in mPFC significantly rescues schizophrenia behaviors in FGR mouse. This study thus provides a potential effective therapy target or strategy for schizophrenia patients induced by FGR

The miR-31/FIH1 pathway involved in TGFβ-induced liver fibrosis

Abstract MicroRNAs (miRNAs) are small, non-coding RNAs that regulate various biological processes, including liver fibrosis. Hepatic stellate cells (HSC) play a central role in the pathogenesis of liver fibrosis. By microarray profiling and real-time PCR, we noted that micorRNA-31 (miR-31) expression was significantly increased during activation of HSC from rat, mouse and human respectively. We found miR-31 was particularly upregulated in HSC but not in Hepatocyte during fibrogenesis. Thus, we hypothesized that miR-31 may mediate liver fibrosis. In our study, we observed that reduction of miR-31 expression significantly inhibited HSC activation while overexpression of its expression obviously promoted HSC activation. Moreover, overexpression of miR-31 promoted HSC migration while inhibition of miR-31 had an opposite effect. The biological function of miR-31 during HSC activation might be through targeting FIH1, a suppressor of hypoxia-inducible factor (HIF-1), as knockdown of FIH1 by short hairpin RNA (shRNA) could mimic the effects of miR-31. In addition, we found that only TGFβ, a pivotal regulator in liver fibrosis, remarkably increased miR-31 expression in HSC. And that the effects of TGFβ upon HSCs can be partially counteracted by inhibition of miR-31. Additionally, ChIP experiments and Luciferase reporter assay demonstrated that Smad3, a major TGF--downstream transcription factor, stimulated the transcription activity of miR-31 by binding directly to the promoter of miR-31. In conclusion, miR-31/FIH1 pathway associates with liver fibrosis, perhaps by participating TGFβ/Smad3 signaling in HSC. A c c e p t e d M a n u s c r i p

A miR-590/Acvr2a/Rad51b Axis Regulates DNA Damage Repair during mESC Proliferation

Embryonic stem cells (ESCs) enable rapid proliferation that also causes DNA damage. To maintain genomic stabilization during rapid proliferation, ESCs must have an efficient system to repress genotoxic stress. Here, we show that withdrawal of leukemia inhibitory factor (LIF), which maintains the self-renewal capability of mouse ESCs (mESCs), significantly inhibits the cell proliferation and DNA damage of mESCs and upregulates the expression of miR-590. miR-590 promotes single-strand break (SSB) and double-strand break (DSB) damage repair, thus slowing proliferation of mESCs without influencing stemness. miR-590 directly targets Activin receptor type 2a (Acvr2a) to mediate Activin signaling. We identified the homologous recombination-mediated repair (HRR) gene, Rad51b, as a downstream molecule of the miR-590/Acvr2a pathway regulating the SSB and DSB damage repair and cell cycle. Our study shows that a miR-590/Acvr2a/Rad51b signaling axis ensures the stabilization of mESCs by balancing DNA damage repair and rapid proliferation during self-renewal

Activation of GSK3β by Sirt2 is required for early lineage commitment of mouse embryonic stem cell.

Sirt2, a member of the NAD(+)-dependent protein deacetylase family, is increasingly recognized as a critical regulator of the cell cycle, cellular necrosis and cytoskeleton organization. However, its role in embryonic stem cells (ESCs) remains unclear. Here we demonstrate that Sirt2 is up-regulated during RA (retinoic acid)-induced and embryoid body (EB) differentiation of mouse ESCs. Using lentivirus-mediated shRNA methods, we found that knockdown of Sirt2 compromises the differentiation of mouse ESCs into ectoderm while promoting mesoderm and endoderm differentiation. Knockdown of Sirt2 expression also leads to the activation of GSK3β through decreased phosphorylation of the serine at position 9 (Ser9) but not tyrosine at position 216 (Tyr216). Moreover, the constitutive activation of GSK3β during EB differentiation mimics the effect of Sirt2 knockdown, while down-regulation of GSK3β rescues the effect of Sirt2 knockdown on differentiation. In contrast to the effect on lineage differentiation, Sirt2 knockdown and GSK3β up-regulation do not change the self-renewal state of mouse ESCs. Overall, our report reveals a new function for Sirt2 in regulating the proper lineage commitment of mouse ESCs