Batista Luciana, Bourachot Brigitte, Mateescu Bogdan, Reyal Fabien, Mechta-Grigoriou Fatima
Stress and Cancer Laboratory, Equipe Labelisée LNCC, Institut Curie, PSL Research University, 26, rue d'Ulm, Paris 75248, France.
Inserm, U830, Paris F-75248, France.
Nat Commun. 2016 Jan 4;7:8959. doi: 10.1038/ncomms9959.
The miR-200 family members have been implicated in stress responses and ovarian tumorigenesis. Here, we find that miR-200c/141 transcription is intimately linked to the transcription of the proximal upstream gene PTPN6 (SHP1) in all physiological conditions tested. PTPN6 and miR-200c/141 are transcriptionally co-regulated by two complementary mechanisms. First, a bypass of the regular PTPN6 polyadenylation signal allows the transcription of the downstream miR-200c/141. Second, the promoters of the PTPN6 and miR-200c/141 transcription units physically interact through a 3-dimensional DNA loop and exhibit similar epigenetic regulation. Our findings highlight that transcription of intergenic miRNAs is a novel outcome of transcriptional read-through and reveal a yet unexplored type of DNA loop associating two closely located promoters. These mechanisms have significant relevance in ovarian cancers and stress response, pathophysiological conditions in which miR-200c/141 exert key functions.
miR-200家族成员与应激反应和卵巢肿瘤发生有关。在此，我们发现，在所有测试的生理条件下，miR-200c/141的转录与近端上游基因PTPN6（SHP1）的转录密切相关。PTPN6和miR-200c/141通过两种互补机制进行转录共调控。首先，绕过常规的PTPN6聚腺苷酸化信号可使下游的miR-200c/141转录。其次，PTPN6和miR-200c/141转录单元的启动子通过三维DNA环发生物理相互作用，并表现出相似的表观遗传调控。我们的研究结果表明，基因间miRNA的转录是转录通读的一个新结果，并揭示了一种尚未被探索的将两个紧密相邻启动子联系起来的DNA环类型。这些机制在卵巢癌和应激反应中具有重要意义，而miR-200c/141在这些病理生理条件中发挥关键作用。
