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Prolyl oligopeptidase (POP) is a multifunctional protease which is involved in many physiological events, but its gene regulatory mechanism is poorly understood. To identify novel regulatory elements of the POP gene, we compared the genomic sequences at the mouse and human POP loci and found six conserved non-coding sequences (CNSs) at adjacent intergenic regions. From these CNSs, four long non-coding RNAs (lncRNAs) were transcribed and the expression pattern of one (lncPrep+96kb) was correlated with that of POP. lncPrep+96kb was transcribed as two forms due to the different transcriptional start sites and was localized at the nucleus and cytoplasm, although more was present at the nucleus. When we knocked down lncPrep+96kb in the primary ovarian granulosa cell and a hepatic cell line, the POP expression was decreased in both cells. In contrast, overexpression of lncPrep+96kb increased the POP expression only in the granulosa cell. Because lncPrep+96kb was upregulated with the same timing as POP in the hormone-treated ovary, this lncRNA could play a role in the POP gene activation in the granulosa cell. Moreover, a downstream region of the human POP gene was also transcribed. We propose a novel mechanism for the POP gene activation.

A long non-coding RNA transcribed from conserved non-coding sequences contributes to the mouse prolyl oligopeptidase gene activation