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Genome-wide integration of microRNA and the transcriptome during human alveolar epithelial cell transdifferentiation identifies SGK1 as novel target of miR- 424/503 [miRNA-array]

ABSTRACT: The alveolar epithelium is comprised of two cell types, alveolar type 1 (AT1) and type 2 (AT2) cells, the latter being capable of self-renewal and transdifferentiation into AT1 fate to establish alveolar function. Micro-RNAs (miRNAs) re critical regulators of developmental pathways, including branching morphogenesis. To determine if miRNAs also play a crucial role in establishment/maintenance of cellular identity within the alveolar epithelium, we performed genome-wide analysis of miRNAs alongside transcriptomic alterations during transdifferentiation of human AT2 (hAT2) into AT1-like cells in vitro . Our results indicated that miRNAs are tightly correlated to known gene expression pattern changes during AEC differentiation. We were able to define three phases of miRNA expression during the trans differentiation process, “early”, “late” and “consistently” changed, which further sub-classified as up- or downregulated. miRNAs with altered expression at all time points during AT1-like differentiation were the largest subgroup, suggesting the need for consistent regulation of signaling pathways to mediate transdifferentiation . Target prediction analysis and integration with previously published gene expression data identified glucocorticoid signaling as the top pathway regulated by miRNAs. Serum/glucocorticoid kinase 1 (SGK1) emerged as a central regulatory factor with temporally-correlated loss of expression and gain of hsa-miR-424 and hsa-miR-503 expression. Functional validation demonstrated specific targeting of these miRNAs to the 3’UTR of SGK1. Taken together, our data show the time-related contribution of miRNAs to the alveolar transdifferentiation process and suggest the need for inhibition of glucocorticoid pathway signaling to achieve the AT1-like cell phenotype in vitro. The miRNA-mRNA interactions identified herein may help to establish AT2 to AT1 cell differentiation in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139968 | GEO | 2020/07/01

REPOSITORIES: GEO

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Project description:Alveoli are thin-walled sacs that serve as the gas exchange units of the lung. They are affected in devastating lung diseases including COPD, Idiopathic Pulmonary Fibrosis, and the major form (adenocarcinoma) of lung cancer, the leading cause of cancer deaths. The alveolar epithelium is composed of two morphologically distinct cell types: alveolar type (AT) 1 cells, exquisitely thin cells across which oxygen diffuses to reach the blood, and AT2 cells, specialized surfactant-secreting cells. Classical studies suggested that AT1 cells arise from AT2 cells during development and following injury, but more recent studies suggest other sources. Here we use histological and marker analysis, lineage tracing, and clonal analysis in mice to identify alveolar progenitor and stem cells and map their locations and potential in vivo. The results show that AT1 and AT2 cells arise independently during development from a bipotential progenitor. After birth, new AT1 cells derive from rare, long-lived, self-renewing AT2 cells, each producing a slowly expanding clonal focus of regenerated alveoli contiguous with the founder AT2 cell. This stem cell function of AT2 cells is broadly activated by diffuse AT1 cell injury, and AT2 self-renewal can be induced in vitro by EGF ligands and permanently activated in vivo by AT2 cell-specific targeting of the oncogenic KrasG12D allele, efficiently transforming AT2 cells into monoclonal adenomatous tumors that rapidly enlarge and prove fatal. Thus, there is a developmental switch in alveolar progenitor cells after birth, when mature AT2 cells function as facultative stem cells that contribute to local alveolar renewal, repair, and cancer. We propose that short-range signals from dying AT1 cells regulate AT2 stem cell activity: a signal transduced by EGFR-KRAS controls AT2 self-renewal and is hijacked during oncogenic transformation, and a separate signal controls reprogramming to AT1 cell fate. To compare expression between ATII and E18 BP populations, RNA was isolated from either population purified by FACS. Two populations are analyzed with 3 biological replicates per population.

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Genome-wide integration of microRNA and the transcriptome during human alveolar epithelial cell transdifferentiation identifies SGK1 as novel target of miR- 424/503 [miRNA-array]

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