GSE125400
A genome-wide long noncoding RNA CRISPRi screen identifies PRANCR as a novel regulator of epidermal homeostasis
Long noncoding RNAs (lncRNAs) are a major component of the noncoding genome, but their functions in human development and disease are still incompletely understood. CRISPR interference screens allow for systematic identification of functional lncRNAs that regulate fundamental biological processes such as tissue development and homeostasis. We identified 2,263 lncRNAs transcribed in human epidermis, and performed a comprehensive CRISPR interference screen against all these elements in primary human epidermal progenitors. Our screen identified 209 lncRNAs controlling epidermal progenitor renewal, with the majority (94%) being positive regulators of proliferation. To validate the results, we performed deeper characterization of a novel lncRNA identified from this screen, PRANCR (LINC01481), using RNA interference-mediated transcript knockdown and phenotype analysis in organotypic human tissue. PRANCR depletion inhibited progenitor proliferation through a G2/M cell cycle arrest, reduced clonogenic potential, and impaired functional epidermal stratification. Transcriptome and computational analysis indicated that PRANCR governs progenitor renewal by controlling the expression of 1,136 genes in trans, in part via the p53-E2F4-CHR pathway. This pathway controls the expression of G2/M cell cycle genes and is a novel mechanism of regulating cell proliferation in epidermal progenitors. Overall design: In this study, we identified 2,263 lncRNAs transcribed in human epidermis, and performed a comprehensive CRISPR interference screen against all these elements in primary human epidermal progenitors.