Dataset Information

Regulation of cell-type-specific transcriptomes by microRNA networks during human brain development.

ABSTRACT: MicroRNAs (miRNAs) regulate many cellular events during brain development by interacting with hundreds of mRNA transcripts. However, miRNAs operate nonuniformly upon the transcriptional profile with an as yet unknown logic. Shortcomings in defining miRNA-mRNA networks include limited knowledge of in vivo miRNA targets and their abundance in single cells. By combining multiple complementary approaches, high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation with an antibody to AGO2 (AGO2-HITS-CLIP), single-cell profiling and computational analyses using bipartite and coexpression networks, we show that miRNA-mRNA interactions operate as functional modules that often correspond to cell-type identities and undergo dynamic transitions during brain development. These networks are highly dynamic during development and over the course of evolution. One such interaction is between radial-glia-enriched ORC4 and miR-2115, a great-ape-specific miRNA, which appears to control radial glia proliferation rates during human brain development.

SUBMITTER: Nowakowski TJ

PROVIDER: S-EPMC6312854 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Regulation of cell-type-specific transcriptomes by microRNA networks during human brain development.

Nowakowski Tomasz J TJ Rani Neha N Golkaram Mahdi M Zhou Hongjun R HR Alvarado Beatriz B Huch Kylie K West Jay A JA Leyrat Anne A Pollen Alex A AA Kriegstein Arnold R AR Petzold Linda R LR Kosik Kenneth S KS

Nature neuroscience 20181119 12

MicroRNAs (miRNAs) regulate many cellular events during brain development by interacting with hundreds of mRNA transcripts. However, miRNAs operate nonuniformly upon the transcriptional profile with an as yet unknown logic. Shortcomings in defining miRNA-mRNA networks include limited knowledge of in vivo miRNA targets and their abundance in single cells. By combining multiple complementary approaches, high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation with an antibod ...[more]

PMID: 30455455

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Project description:Microglial cells form a context-dependent network of brain immunoeffector cells. Despite their indispensable roles, unresolved questions exist around biomarker discovery relevant to their cellular localization, self-renewing potential, and brain developmental dynamics. To resolve the existent gap in the annotation of candidate biomarkers, we conducted a meta-analysis of brain cells using available high-throughput data sets for deciphering microglia-specific expression profiles. We have identified 3,290 significant genes specific to microglia and further selected the top 20 dysregulated genes on the basis of p-value and log2FC. To this list, we added 7 known microglia-specific markers making the candidate list comprising 27 genes for further downstream analyses. Next, we established a connectome of these potential markers with their putative protein partners, which demonstrated strong associations of upregulated genes like Dedicator of cytokinesis 2 (DOCK2) with early/mature microglial markers such as Sphingosine kinase 1 (SPHK1), CD68, and CD45. To elucidate their respective brain anatomical location, we deconvoluted the BrainSpan Atlas expression data. This analysis showed high expression of the majority of candidate genes in microglia-dense regions (Amygdala, Hippocampus, Striatum) in the postnatal brain. Furthermore, to decipher their localized expression across brain ages, we constructed a developmental dynamics map (DDM) comprising extensive gene expression profiles throughout prenatal to postnatal stages, which resulted in the discovery of novel microglia-specific gene signatures. One of the interesting readout from DDM is that all the microglia-dense regions exhibit dynamic regulation of few genes at 37 post conception week (pcw), the transition period between pre- and postnatal stages. To validate these findings and correlate them as potential biomarkers, we analyzed the expression of corresponding proteins in hESC-derived human microglia precursors. The cultured microglial precursors showed expression of Pentraxin 3 (PTX3) and SPHK1 as well as several known markers like CD68, Allograft inflammatory factor 1 (AIF1/IBA1). In summary, this study has furnished critical insights into microglia dynamics across human brain ages and cataloged potential transcriptomic fingerprints that can be further exploited for designing novel neurotherapeutics.

Dataset Information

Regulation of cell-type-specific transcriptomes by microRNA networks during human brain development.

Publications

Regulation of cell-type-specific transcriptomes by microRNA networks during human brain development.

Similar Datasets

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