Unraveling the dark matter, long non-coding RNAs, in male reproductive diseases: A narrative review

Recent advances in human transcriptome have revealed the fundamental and functional roles of long non-coding RNA in the susceptibility to diverse diseases and pathological conditions. They participate in wide range of biological processes such as the modulating of chromatin structure, transcription, translation, and posttranslation modification. In addition, based on their unique expression profiles and their association with clinical abnormalities such as those of related to male reproductive diseases, they can be used to develop therapeutic methods and biomarkers for screening of the diseases. In this study, we will review the identified lncRNAs and their molecular functions in the pathogenesis of male reproductive diseases such as prostate cancer, benign prostatic hyperplasia, prostatitis, testicular cancer, varicocele, and sperm abnormalities. Key words: Long noncoding RNA, Prostate cancer, Prostatic hyperplasia, Prostatitis, Varicocele, Sperm abnormalities.

Age-related pacemaker deterioration is due to impaired intracellular and membrane mechanisms: Insights from numerical modeling

Age-related deterioration of pacemaker function has been documented in mammals, including humans. In aged isolated sinoatrial node tissues and cells, reduction in the spontaneous action potential (AP) firing rate was associated with deterioration of intracellular and membrane mechanisms; however, their relative contribution to age-associated deficient pacemaker function is not known. Interestingly, pharmacological interventions that increase posttranslation modification signaling activities can restore the basal and maximal AP firing rate, but the identities of the protein targets responsible for AP firing rate restoration are not known. Here, we developed a numerical model that simulates the function of a single mouse pacemaker cell. In addition to describing membrane and intracellular mechanisms, the model includes descriptions of autonomic receptor activation pathways and posttranslation modification signaling cascades. The numerical model shows that age-related deterioration of pacemaker function is related to impaired intracellular and membrane mechanisms: HCN4, T-type channels, and phospholamban functions, as well as the node connecting these mechanisms, i.e., intracellular Ca2+ and posttranslation modification signaling. To explain the restored maximal beating rate in response to maximal phosphodiesterase (PDE) inhibition, autonomic receptor stimulation, or infused cyclic adenosine monophosphate (cAMP), the model predicts that phospholamban phosphorylation by protein kinase A (PKA) and HCN4 sensitivity to cAMP are altered in advanced age. Moreover, alteration in PKA and cAMP sensitivity can also explain age-reduced sensitivity to PDE inhibition and autonomic receptor stimulation. Finally, the numerical model suggests two pharmacological approaches and one gene manipulation method to restore the basal beating rate of aged pacemaker cells to that of normal adult cells. In conclusion, our numerical model shows that impaired membrane and intracellular mechanisms and the nodes that couple them can lead to deteriorated pacemaker function. By increasing posttranslation modification signaling, the deteriorated basal and maximal age-associated beating rate can be restored to adult levels.

Mining the Virgin Land of Neurotoxicology: A Novel Paradigm of Neurotoxic Peptides Action on Glycosylated Voltage-Gated Sodium Channels

Voltage-gated sodium channels (VGSCs) are important membrane protein carrying on the molecular basis for action potentials (AP) in neuronal firings. Even though the structure-function studies were the most pursued spots, the posttranslation modification processes, such as glycosylation, phosphorylation, and alternative splicing associating with channel functions captured less eyesights. The accumulative research suggested an interaction between the sialic acids chains and ion-permeable pores, giving rise to subtle but significant impacts on channel gating. Sodium channel-specific neurotoxic toxins, a family of long-chain polypeptides originated from venomous animals, are found to potentially share the binding sites adjacent to glycosylated region on VGSCs. Thus, an interaction between toxin and glycosylated VGSC might hopefully join the campaign to approach the role of glycosylation in modulating VGSCs-involved neuronal network activity. This paper will cover the state-of-the-art advances of researches on glycosylation-mediated VGSCs function and the possible underlying mechanisms of interactions between toxin and glycosylated VGSCs, which may therefore, fulfill the knowledge in identifying the pharmacological targets and therapeutic values of VGSCs.

The Deubiquitylation Activity of Ubp8 Is Dependent upon Sgf11 and Its Association with the SAGA Complex

ABSTRACT Covalent modifications of the histone tails and the cross talk between these modifications are hallmark features of gene regulation. The SAGA histone acetyltransferase complex is one of the most well-characterized complexes involved in these covalent modifications. The recent finding that the removal of the ubiquitin group from H2B is performed by a component of SAGA, Ubp8, is intriguing as it assigns two posttranslation modification processes to one complex. In this work, we characterize the association of Ubp8 with SAGA and the effect that acetylation and deubiquitylation have on one another in vitro and in vivo. We found not only that Ubp8 is a part of the SAGA complex, but also that its deubiquitylation activity requires Ubp8's association with SAGA. Furthermore, we found that the Ubp8 association with SAGA requires Sgf11 and that this requirement is reciprocal. We also found that the acetylation and deubiquitylation activities of SAGA are independent of one another. However, we found that preacetylating histone H2B inhibited subsequent deubiquitylation. Additionally, we found that increasing the ubiquitylation state of H2B inhibited the expression of the ARG1 gene, whose repression was previously shown to require the RAD6 ubiquitin ligase. Taken together, these data indicate that the expression of some genes, including ARG1, is regulated by a balance of histone H2B ubiquitylation in the cell.

Phosphorylation of Nuclear MyoD Is Required for Its Rapid Degradation

ABSTRACT MyoD is a basic helix-loop-helix transcription factor involved in the activation of genes encoding skeletal muscle-specific proteins. Independent of its ability to transactivate muscle-specific genes, MyoD can also act as a cell cycle inhibitor. MyoD activity is regulated by transcriptional and posttranscriptional mechanisms. While MyoD can be found phosphorylated, the functional significance of this posttranslation modification has not been established. MyoD contains several consensus cyclin-dependent kinase (CDK) phosphorylation sites. In these studies, we examined whether a link could be established between MyoD activity and phosphorylation at putative CDK sites. Site-directed mutagenesis of potential CDK phosphorylation sites in MyoD revealed that S200 is required for MyoD hyperphosphorylation as well as the normally short half-life of the MyoD protein. Additionally, we determined that turnover of the MyoD protein requires the proteasome and Cdc34 ubiquitin-conjugating enzyme activity. Results of these studies demonstrate that hyperphosphorylated MyoD is targeted for rapid degradation by the ubiquitin pathway. The targeted degradation of MyoD following CDK phosphorylation identifies a mechanism through which MyoD activity can be regulated coordinately with the cell cycle machinery (CDK2 and CDK4) and/or coordinately with the cellular transcriptional machinery (CDK7, CDK8, and CDK9).