Noncoding RNAs: Regulators of the Mammalian Transcription Machinery

Abstract

Transcription by RNA polymerase II (Pol II) is required to produce mRNAs and some noncoding RNAs (ncRNAs) within mammalian cells. This coordinated process is precisely regulated by multiple factors, including many recently discovered ncRNAs. In this perspective, we will discuss newly identified ncRNAs that facilitate DNA looping, regulate transcription factor binding, mediate promoter-proximal pausing of Pol II, and/or interact with Pol II to modulate transcription. Moreover, we will discuss new roles for ncRNAs, as well as a novel Pol II RNA-dependent RNA polymerase activity that regulates an ncRNA inhibitor of transcription. As the multifaceted nature of ncRNAs continues to be revealed, we believe that many more ncRNA species and functions will be discovered.

Keywords: RNA polymerase II; circular RNAs; divergent RNAs; enhancer RNAs; tethered RNAs.

Figure 1

Noncoding RNAs (ncRNAs) influence multiple steps in mammalian RNA polymerase II (Pol II) transcription. A) Enhancer RNAs (eRNAs) facilitate gene looping in activate transcription of nearby genes. eRNAs enhance gene looping by interacting with Mediator, such as Kallikrein-related peptidase 3 (KLK3) eRNA and activating ncRNA-7 (ncRNA-a7). Alternatively, eRNAs like NRIP1 eRNA can also interact with cohesin. B) ncRNAs regulate the transition of promoter-proximal paused Pol II to elongating Pol II. 7SK RNA sequesters the positive transcription elongation factor b (P-TEFb) to inhibit phosphorylation of the Pol II C-terminal domain (CTD; phosphorylation is indicated by yellow circles) and subsequent transition into the elongation phase of transcription. The negative elongation factor (NELF) is recruited to Pol II, possibly through interactions with nascent RNA, and inhibits Pol II elongation. The Activity-regulated cytoskeletal protein (Arc) eRNA acts as an RNA decoy to bind NELF and prevent NELF-mediated Pol II pausing. C) ncRNAs influence the association of transcription factors (TFs) with DNA. Gas5 ncRNA binds to the glucocorticoid receptor (GR) DNA-binding domain to block GR from interacting with DNA. Tethered ncRNAs, possibly bound to Pol II, interact with Yin-Yang 1 (YY1) and facilitate recruitment to its DNA-binding site. The viral EBV-encoded RNA 2 (EBER2) ncRNA interacts with nascent viral RNA to recruit PAX5 to viral chromatin. D) ncRNAs directly interact with Pol II to inhibit or enhance transcription. B2 RNA prevents Pol II from making important contacts with DNA, inhibiting transcription. Pol II RNA-dependent RNA polymerase (RdRP) activity produces extended B2 RNA (eB2 RNA), which is then released by an unknown cellular factor, possibly allowing freed Pol II to resume transcription. Circular RNAs (circRNAs), including circular intronic RNAs (ciRNAs) and exon intron circular RNAs (EIciRNAs), associate with Pol II to facilitate transcription of their parental mRNAs. EIciRNAs interact with Pol II through the U1 small nuclear ribonucleoprotein (snRNP) complex to enhance transcription.