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Transcriptomic analysis of miR-19a-19b-20a subcluster-overexpressed fibroblasts in bleomycin-induced lung fibrosis

ABSTRACT: Lung fibroblasts play a pivotal role in pulmonary fibrosis, a devastating lung diseases, by producing extracellular matrix. MicroRNAs (miRNAs) suppress a lot of genes posttranscriptionally, but the dynamics and the role of miRNAs in activated lung fibroblasts in fibrotic lung has been poorly understood. We found miR-19a, 19b and 20a subcluster expression increased in activated lung fibroblasts as the fibrosis progression. To elucidate whether fibroblast-specific intervention against miR-19a, 19b and 20a subcluster modulates pathogenic activation of lung fibroblasts in vivo, we intratracheally-transferred the subcluster-overexpressed fibroblasts into bleomycin-treated lungs and performed global transcriptome analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE100116 | GEO | 2018/11/20

REPOSITORIES: GEO

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Project description:The B1 SOX transcription factors SOX1/2/3/19 have been implicated in various processes of early embryogenesis. However, their regulatory functions in stages from the blastula to early neurula remain largely unknown, primarily because loss-of-function studies have not been informative to date. In our present study, we systematically knocked down the B1 sox genes in zebrafish. Only the quadruple knockdown of the four B1 sox genes sox2/3/19a/19b, which are active in the early embryo, resulted in very severe developmental abnormalities, confirming that the B1 sox genes are functionally redundant. We characterized the sox2/3/19a/19b quadruple knockdown embryos in detail by examining the changes in gene expression through microarray analysis as well as in situ hybridization. Importantly, these phenotypic analyses of the quadruple knockdown embryos reveled that the B1 SOX proteins regulate the following distinct processes: (1) early dorsoventral patterning by controlling bmp2b/7; (2) gastrulation movements via the regulation of pcdh18a/18b and non-canonical wnt genes; (3) neural differentiation by regulating the Hes-class bHLH gene her3 and the proneural-class bHLH genes neurog1 (positively) and ascl1a (negatively), and regional transcription factor genes, e.g. hesx1, zic1 and rx3; and (4) neural patterning by regulating signaling pathway genes, cyp26a1 in RA signaling, oep in Nodal signaling, shh, and mdkb. These findings indicate that the B1 SOX proteins control a wide range of developmental regulators in the early embryo and suggest that the B1 sox functions are central to coordinating cell fate specification with patterning and morphogenetic processes occurring in the early embryo. Microarray analysis was carried out to compare gene expression profiles at the 30% epiboly (30%E), 75% epiboly (75%E) and tailbud (TB) stages between wild-type embryos and the sox2/3/19a/19b quadruple knockdown embryos. RNAs from two independent samples were analyzed for each embryonic stage.

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Transcriptomic analysis of miR-19a-19b-20a subcluster-overexpressed fibroblasts in bleomycin-induced lung fibrosis

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