Transcriptional gene silencing through epigenetic changes mediated by non-coding RNAs

Abstract

Chromatin remodeling guided by non-coding RNA (ncRNA) contributes mechanistically to the establishment of chromatin structure and to the maintenance of epigenetic memory. Various ncRNAs have been identified as regulators of chromatin structure and gene expression. The widespread occurrence of antisense transcription in eukaryotes emphasizes the prevalence of gene regulation by natural antisense transcripts. Recently, antisense ncRNAs have been implicated in the silencing of tumor suppressor genes through epigenetic remodeling events. Characterization of the antisense RNAs involved in the development or maintenance of oncogenic states may define ncRNAs as early biomarkers for the emergence of cancer, and could have a significant impact on the development of tools for disease diagnosis and treatment. In this review, current knowledge on the mechanisms of ncRNA-mediated transcriptional gene silencing in humans is discussed, and parallels between the establishment of a silent chromatin state mediated by siRNAs and long antisense ncRNAs are highlighted.

Figure 1. A model for the antisense non-coding RNA-mediated initiation of transcriptional gene silencing in human cells

Antisense RNA associates with the argonaute 1 (Ago1) protein. The RNA-Ago1 complex then targets the nascent promoter-associated RNA, which is transcribed by RNA polymerase II (RNAPII) in the sense direction. Subsequently, the putative silencing complex, which may consist of the PRC2 Polycomb complex (composed of KMT6 [Ezh2], SUZ12 and EED), HDAC1, the DNA methyltransferases Dnmt3A and Dnmt1 and the histone methyltransferases KMT1C (G9a) and/or KMT1A (Suv39h1), is recruited to the promoter. Recruitment of the silencing complex may be mediated through the interaction of Ago1 with Dnmt3a, or directly through promoter-associated RNA. HDAC1-mediated histone deacetylation may precede histone H3 methylation at Lys⁹ and Lys²⁷ (H3K9me2 and H3K27me3, respectively) of the nucleosomes proximal to the promoter target site. Histone methylation may be mediated by the candidate lysine methyltransferases KMT6 (for H3K27) and KMT1C (for H3K9) and/or KMT1A (alternative H3K9 methyltransferases are shown in white), leading to the formation of heterochromatin at the target promoter. The associations of protein subunits indicate known interactions.