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Let-7 and miR-125 cooperate to promote astrogliogenesis

ABSTRACT: The molecular basis of astrocyte differentiation and maturation is poorly understood. Here we set out to study miRNA function during the glial progenitor cell (GPC) to astrocyte transition. Inducible deletion of all canonical microRNAs in GPCs in vitro led to a block in the differentiation to astrocytes. In an unbiased screen, the reintroduction of let-7 and miR-125 families of microRNAs rescued differentiation. Let-7 and miR-125 shared many targets and functioned in parallel to JAK-STAT signaling, a known regulator of astrogliogenesis. While individual knockdown of shared targets did not rescue the differentiation phenotype in microRNA-deficient GPCs, overexpression of these targets in wild-type GPCs blocked differentiation. This finding supports the idea that microRNAs simultaneously suppress multiple mRNAs that inhibit differentiation. The microRNA-regulated targets were enriched for genes downregulated during in vivo astrocyte differentiation and upregulated in glioblastomas, consistent with validity of using the in vitro model to study in vivo events. These findings provide insight into the microRNAs and the genes they regulate in this important cell fate transition.

ORGANISM(S): Mus musculus

PROVIDER: GSE64637 | GEO | 2015/03/05

SECONDARY ACCESSION(S): PRJNA271487

REPOSITORIES: GEO

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Project description:The regulation of gene expression in cells, including by microRNAs (miRNAs), is a dynamic process. Current methods for identifying microRNA targets by combining sequence, miRNA and mRNA expression data do not adequately utilize the temporal information and thus miss important miRNAs and their targets. We developed a new method, mirDREM, that uses probabilistic modeling to reconstruct dynamic regulatory networks which explain how temporal gene expression is jointly regulated by microRNAs and transcription factors (TFs). We used mirDREM to study the regulation of postnatal lung development in mice. The reconstructed network for this process identified several known miRNAs and TFs and provided novel predictions about additional miRNAs and the specific developmental phases they regulate. Microarray data of Mouse Lung Epithelial cells MLE-12 after transfection with inhibitors for miR-30a, miR-30d, miR-23b and miR-125 and with precursors for miR-337, miR-466a, miR466d and miR-476c. The results provide a general insight into the gene expression profile which was modulated by the inhibition or overexpression of these microRNAs. We experimentally validated several predictions and show that miR-30d, miR-30a, and miR-467c are new regulators of proliferation in lung cells. Our analysis establishes new links between identified miRNAs and lung diseases, supporting recent evidence that such diseases may represent reversal of lung differentiation. We first analyzed the endogenous expression of miR-30a, miR-30d, miR-23b, miR-125, miR-337, miR-466a, miR466d and miR-476c in MLE-12 cells. Then, we transfected the MLE-12 cells with inhibitors ( miR-30a, miR-30d, miR-23b and miR-125) for the highly expressed and precursos for those that were almost undetectable (miR-337, miR-466a, miR466d and miR-476c). RNA level of the 8 microRNAs was verify by qRT-PCR in order to validate the transfection efficiency. Finally, 0.5ug of total RNA was used to performe the gene expression microarrays for each condition

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Let-7 and miR-125 cooperate to promote astrogliogenesis

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