Slow Transcription of the 99a/let-7c/125b-2 Cluster Results in Differential MiRNA Expression and Promotes Melanoma Phenotypic Plasticity
| Autor: | Hagar Malcov-Brog, Amitai Menuchin, Carmit Levy, Lital Shaham, Nadav Elkoshi, Shmuel Ruppo, Jeffrey W. Taub, Sharona Elgavish, Roma Parikh, Rachel E. Bell, Shivang Parikh, Tamar Golan, Oxana Kapitansky, Yuval Nevo, Guy Shapira, Shai Izraeli, Noam Shomron, Danna Sheinboim |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
TRIM28 Transcription Genetic RNA polymerase II Dermatology Tripartite Motif-Containing Protein 28 Biochemistry Transcriptome 03 medical and health sciences Mice 0302 clinical medicine Transcription (biology) Cell Line Tumor microRNA Animals Humans Molecular Biology Gene Melanoma Microphthalmia-Associated Transcription Factor biology Cell Biology Microphthalmia-associated transcription factor Phenotype Adaptation Physiological Cell biology MicroRNAs 030104 developmental biology HEK293 Cells 030220 oncology & carcinogenesis biology.protein Female |
| Zdroj: | The Journal of investigative dermatology. 141(12) |
| ISSN: | 1523-1747 |
| Popis: | Almost half of the human microRNAs (miRNAs) are encoded in clusters. Although transcribed as a single unit, the levels of individual mature miRNAs often differ. The mechanisms underlying differential biogenesis of clustered miRNAs and the resulting physiological implications are mostly unknown. In this study, we report that the melanoma master transcription regulator MITF regulates the differential expression of the 99a/let-7c/125b-2 cluster by altering the distribution of RNA polymerase II along the cluster. We discovered that MITF interacts with TRIM28, a known inhibitor of RNA polymerase II transcription elongation, at the mIR-let-7c region, resulting in the pausing of RNA polymerase II activity and causing an elevation in mIR-let-7c expression; low levels of RNA polymerase II occupation over miR-99a and miR-125b-2 regions decreases their biogenesis. Furthermore, we showed that this differential expression affects the phenotypic state of melanoma cells. RNA-sequencing analysis of proliferative melanoma cells that express miR-99a and miR-125b mimics revealed a transcriptomic shift toward an invasive phenotype. Conversely, expression of a mIR-let-7c mimic in invasive melanoma cells induced a shift to a more proliferative state. We confirmed direct target genes of these miRNAs, including FGFR3, BAP1, Bcl2, TGFBR1, and CDKN1A. Our study demonstrates an MITF-governed biogenesis mechanism that results in differential expression of clustered 99a/let-7c/125b-2 miRNAs that control melanoma progression. |
| Databáze: | OpenAIRE |
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