Abstract
Though miR-205 function has been largely characterized, the nature of its host gene, MIR205HG, is still completely unknown. Here, we show that only lowly expressed alternatively spliced MIR205HG transcripts act as de facto pri-miRNAs, through a process that involves Drosha to prevent unfavorable splicing and directly mediate miR-205 excision. Notably, MIR205HG-specific processed transcripts revealed to be functional per se as nuclear long noncoding RNA capable of regulating differentiation of human prostate basal cells through control of the interferon pathway. At molecular level, MIR205HG directly binds the promoters of its target genes, which have an Alu element in proximity of the Interferon-Regulatory Factor (IRF) binding site, and represses their transcription likely buffering IRF1 activity, with the ultimate effect of preventing luminal differentiation. As MIR205HG functions autonomously from (albeit complementing) miR-205 in preserving the basal identity of prostate epithelial cells, it warrants reannotation as LEADeR (Long Epithelial Alu-interacting Differentiation-related RNA).
Highlights
Though miR-205 function has been largely characterized, the nature of its host gene, MIR205HG, is still completely unknown
In this work we characterize for the first time the expression pattern and role of MIR205HG, showing that (i) MIR205HG is mainly expressed in the basal layer of prostate epithelium and lost in prostate adenocarcinoma (PRAD), (ii) the Drosha-mediated processing of specific alternative transcripts of the gene is responsible for miR-205 production, and (iii) MIR205HG functions independently of the hosted miRNA as nuclear intergenic long noncoding RNA capable of regulating basal-luminal differentiation through repression of the interferon pathway
Interrogation of publicly available transcriptomic data revealed that LEADR/MIR205HG is normally expressed in epithelia such as skin, prostate and breast, and almost absent in tissues of different embryonic origin (Fig. 1a)
Summary
Though miR-205 function has been largely characterized, the nature of its host gene, MIR205HG, is still completely unknown. MIR205HG-specific processed transcripts revealed to be functional per se as nuclear long noncoding RNA capable of regulating differentiation of human prostate basal cells through control of the interferon pathway. As MIR205HG functions autonomously from (albeit complementing) miR-205 in preserving the basal identity of prostate epithelial cells, it warrants reannotation as LEADeR (Long Epithelial Alu-interacting Differentiation-related RNA). In this work we characterize for the first time the expression pattern and role of MIR205HG, showing that (i) MIR205HG is mainly expressed in the basal layer of prostate epithelium and lost in PRAD, (ii) the Drosha-mediated processing of specific alternative transcripts of the gene is responsible for miR-205 production, and (iii) MIR205HG functions independently of the hosted miRNA as nuclear intergenic long noncoding RNA (lincRNA) capable of regulating basal-luminal differentiation through repression of the interferon pathway. Because MIR205HG processed transcript operates autonomously from miR-205, we will refer to it as LEADeR (LEADR)
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