hnRNP R negatively regulates transcription by modulating the association of P‐TEFb with 7SK and BRD4

Abstract

The P‐TEFb complex promotes transcription elongation by releasing paused RNA polymerase II. P‐TEFb itself is known to be inactivated through binding to the non‐coding RNA 7SK but there is only limited information about mechanisms regulating their association. Here, we show that cells deficient in the RNA‐binding protein hnRNP R, a known 7SK interactor, exhibit increased transcription due to phosphorylation of RNA polymerase II. Intriguingly, loss of hnRNP R promotes the release of P‐TEFb from 7SK, accompanied by enhanced hnRNP A1 binding to 7SK. Additionally, we found that hnRNP R interacts with BRD4, and that hnRNP R depletion increases BRD4 binding to the P‐TEFb component CDK9. Finally, CDK9 is stabilized upon loss of hnRNP R and its association with Cyclin K is enhanced. Together, our results indicate that hnRNP R negatively regulates transcription by modulating the activity and stability of the P‐TEFb complex, exemplifying the multimodal regulation of P‐TEFb by an RNA‐binding protein.

Pan‐cancer analysis of the oncogenic role of HNRNPR in human tumors

“…In addition to its role in tumors, growing evidence has demonstrated that HNRNPR plays a significant role in different physiological as well as pathophysiological processes, such as transcription (Ji et al, 2022), translation (Chung et al, 2019), and mRNA stability (Cao et al, 2022). Above all, HNRNPR was proved to be multifunctional in diverse regulatory mechanisms, and no systematic study of HNRNPR in pan-cancer has been reported yet.…”

“…Increasing evidence has revealed that HNRNPR displays diverse cellular functions and widely participates in both physiological and pathophysiological processes. HNRNPR modulates transcription activation via the balance between 7SK/P‐TEFb and 7SK/hnRNP (Ji et al, 2022), promotes transcriptional activity of the c‐fos promoter (Fukuda et al, 2009), regulates the local messenger RNA (mRNA) availability and translation activity in axons (Chung et al, 2019), enhances LDLR stability through its 5'‐UTR RNA regions to affect lipid metabolism (Cao et al, 2022), participates in neuronal cholesterol metabolism by exerting repressive activity on HMGCR (Agbo et al, 2021). Missense or truncating of HNRNPR is associated with developmental defects, such as brain abnormalities (Duijkers et al, 2019).…”

Conserved role of hnRNPL in alternative splicing of epigenetic modifiers enables B cell activation

“…Notably, at least 9 of the 15 genes with conserved splicing changes encoded for proteins that can affect gene expression (bolded genes in the inset of Fig. 6E ), including those encoding H3K27 demethylase KDM6A and transcriptional coactivator GPBP1 (Hsu et al, 2003 ) in eight datasets, as well as H3K36 methyltransferase NSD2 , splicing factor and transcriptional regulator HNRNPR (Ji et al, 2022 ), histone and non-histone protein deacetylase SIRT1 (Wang et al, 2019 ; Gan et al, 2020 ), the NuA4/TIP60 complex subunit EPC1 , and the H3K14ac histone reader BAZ2B that is part of chromatin remodeling complexes (Oppikofer et al, 2017 ) (Figs. 6E,G and EV4B; Dataset EV5 ).…”

Targeting BRD4 attenuates the stemness and aggressiveness of ameloblastoma

“…The primary function of BRD4 involves organizing super‐enhancers (SEs) and regulating oncogene expression (Di Micco et al, 2014; Donati et al, 2018). Specifically, as an epigenetic reader, BRD4 recognizes acetylated lysine residues on histones H3 and H4 (Shi & Vakoc, 2014) and mediates transcription initiation and elongation after recruiting the Mediator complex, positive transcription elongation factor b (P‐TEFb) and RNA polymerase II (Ji et al, 2022; Khoueiry et al, 2019). According to recent studies, BRD4 may contribute to the progression of breast cancer, gastric cancer, ovarian cancer, and head and neck squamous cell carcinoma (Drumond‐Bock & Bieniasz, 2021; Nagarajan et al, 2020; Qin et al, 2019; Zhang et al, 2022).…”