TDP-43 regulates cancer-associated microRNAs

regulation of miRNA genes contributes to pathogenesis of a wide range of human diseases, including cancer. The TAR DNA binding protein 43 （TDP- 43）, a RNAJDNA binding protein associated with neu- rodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs regulated by TDP- 43 using RNA-Seq coupled with an siRNA-mediated knockdown approach. TDP-43 knockdown affected the expression of a number of miRNAs. In addition, TDP-43 down-regulation led to alterations in the patterns of dif- ferent isoforms of miRNAs （isomiRs） and miRNA arm selection, suggesting a previously unknown role of TDP- 43 in miRNA processing. A number of TDP-43 associ- ated miRNAs, and their candidate target genes, are associated with human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulat- ing miR-423-3p. In contrast, TDP-43 increases miR-500a- 3p expression and binds to the mature miR-500a-3p sequence. Reduced expression of miR-500a-3p is associated with poor survival of lung cancer patients,suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Cancer-associated genes LIF and PAPPA are possible targets of miR-500a- 3p. Our work suggests that TDP-43-regulated miRNAs may play multifaceted roles in the pathogenesis of cancer.

MiR-130a regulates and dendritic spine MeCP2 neurite outgrowth density by targeting

MicroRNAs （miRNAs） are critical for both development and function of the central nervous system. Significant evidence suggests that abnormal expression of miRNAs is associated with neurodevelopmental disorders. MeCP2 protein is an epigenetic regulator repressing or activating gene transcription by binding to methylated DNA. Both loss-of-function and gain-of-function muta- tions in the MECP2 gene lead to neurodevelopmental disorders such as Rett syndrome, autism and MECP2 duplication syndrome. In this study, we demonstrate that miR-130a inhibits neurite outgrowth and reduces dendritic spine density as well as dendritic complexity. Bioinformatics analyses, cell cultures and biochemical experiments indicate that miR-130a targets MECP2 and down-regulates MeCP2 protein expression. Further- more, expression of the wild-type MeCP2, but not a loss- of-function mutant, rescues the miR-130a-induced phe- notype. Our study uncovers the MECP2 gene as a pre- vious unknown target for miR-130a, supporting that miR-130a may play a role in neurodevelopment by reg- ulating MeCP2. Together with data from other groups,our work suggests that a feedback regulatory mecha- nism involving both miR-130a and MeCP2 may serve to ensure their appropriate expression and function in neural development.