A Long Noncoding RNA, lncRNA205, and an Embedded MicroRNA, MiR-205 have Overlapping and Distinct Contributions to Thymopoiesis and Development

Abstract

MiR-205 is an epithelial-specific microRNA (miR) that supports thymopoiesis. This miR positively regulates Forkhead Box N1 (Foxn1) transcription factor expression. MiR-205 is embedded in a long noncoding RNA (lncRNA), termed MIR205HG in humans. Several lncRNAs that contain miRs have independent functional roles in tissue development and/or regeneration. We characterized the transcriptome assembly of the murine locus containing miR-205 and the larger lncRNA. Conditional knockout mice that harbored a targeted deletion of the proximal region of the lncRNA, with miR-205 sequences retained, were developed. The phenotypes in these mice were compared to those with a miR-205 deficiency. The more severe stress-induced thymic atrophy reported in miR-205-deficient mice, compared to littermate controls, is also evident in lncRNA205 knockout lines. In contrast, a lncRNA205 deficiency results in a smaller mouse stature, which may be coupled with a reduced fat but normal lean mass. These phenotypic differences are explained, in part, by the differential regulation of the lncRNA transcript relative to the pre-mature miR-205. Interferon and IL-22, cytokines released following inflammation, transiently reduce miR-205 while increasing the lncRNA. This is partly determined by the DNp63 transcription factor, which controls miR-205 expression. Gene expression comparisons are being undertaken to reveal how the transcriptome is differentially regulated by these two non-coding RNA species. Further, the mechanism by which these noncoding RNAs regulate Foxn1 is being elucidated. Taken together, these findings suggest both overlapping and independent functions for the lncRNA205 and the embedded miR-205.