RNA fate determination through cotranscriptional adenosine methylation and microprocessor binding

Knuckles, Philip; Carl, Sarah H.; Musheev, Michael U.; Niehrs, Christof; Wenger, Alice; Bühler, Marc

doi:10.1038/nsmb.3419

Cited by 130 publications

(130 citation statements)

References 63 publications

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“…Minimal differences were noted on the content and the location of m 6 A in cytoplasmic mRNA and chromatin-associated nascent pre-mRNA or nucleoplasmic mRNA at steady-state [16], suggesting that m 6 A methylation occurred co-transcriptionally. This idea was supported by recent studies that METTL3 interacted with chromatin and the transcription machinery [17][18][19].…”

Section: Mettl3supporting

confidence: 69%

RNA m6A modification and its function in diseases

2018

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Section: Mettl3supporting

confidence: 69%

RNA m6A modification and its function in diseases

2018

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“…Besides their key roles in siRNA/miRNA biogenesis, RNAi factors also promote transcription termination (Skourti-Stathaki et al, 2014) and degradation of nascent transcripts (Knuckles et al, 2017). Antisense transcription, induced by R-loops, may result in the formation of transient double-stranded RNA, which in turn can attract Dicer-Argonaute machinery and promote H3K9me2 deposition and HP1γ recruitment, effectively creating localized patches of heterochromatin (Skourti-Stathaki et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Intragenic Enhancers Attenuate Host Gene Expression

et al. 2017

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SUMMARY Eukaryotic gene transcription is regulated at many steps, including RNA Polymerase II (RNAPII) recruitment, transcription initiation, promoter-proximal RNAPII pause release, and transcription termination; however, mechanisms regulating transcription during productive elongation remain poorly understood. Enhancers, which activate gene transcription, themselves undergo RNAPII-mediated transcription, but our understanding of enhancer transcription and enhancer RNAs (eRNAs) remain incomplete. Here we show that transcription at intragenic enhancers interferes with and attenuates host gene transcription during productive elongation. While the extent of attenuation correlates positively with nascent eRNA expression, the act of intragenic enhancer-transcription alone, but not eRNAs, explains the attenuation. Through CRISPR/Cas9-mediated deletions, we demonstrate a physiological role for intragenic enhancer-mediated transcription attenuation in cell-fate determination. We propose that intragenic enhancers not only enhance transcription of one or more genes from a distance but also fine-tune transcription of their host gene through transcription interference, facilitating differential utilization of the same regulatory element for disparate functions.

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“…The prevalent internal RNA modification mark N(6)-methyladenosine (m 6 A) has been reported to play a role in regulating most facets of the RNA life cycle, including regulation of pre-mRNA splicing, mRNA stability, and mRNA translation (Lin et al, 2016;Liu et al, 2015;Wang et al, 2015Wang et al, , 2014Xiao et al, 2016;Zhao et al, 2014). Recently, work by us (Alarcón et al, 2015) and others (Ke et al, 2017;Knuckles et al, 2017) has established that m 6 A marks are deposited in the nucleus and are proposed to function in many nuclear regulatory processes, including microRNA and messenger RNA processing. Despite the widespread use of these pathways, the underlying regulatory programs that influence m 6 A deposition patterns across the transcriptome are poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Fish

Nguyen

Zhang

et al. 2018

Preprint

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SUMMARYPost-transcriptional regulation of RNA stability is a key step in gene expression control. We describe a regulatory program, mediated by the double-stranded RNA binding protein TARBP2, that controls RNA stability in the nucleus. TARBP2 binding to pre-mRNAs results in increased intron retention, subsequently leading to targeted degradation of TARBP2-bound transcripts. This is mediated by TARBP2 recruitment of the m 6 A RNA methylation machinery to its target transcripts, where deposition of m 6 A marks influences the recruitment of splicing regulators, inhibiting efficient splicing. Interactions between TARBP2 and the nucleoprotein TPR then promote degradation of these TARBP2-bound transcripts by the nuclear exosome. Additionally, analysis of clinical gene expression datasets revealed a functional role for this TARBP2 pathway in lung cancer. Using xenograft mouse models, we find that TARBP2 impacts tumor growth in the lung, and that this function is dependent on TARBP2-mediated destabilization of ABCA3 and FOXN3. Finally, we establish the transcription factor ZNF143 as an upstream regulator of TARBP2 expression. RESEARCH HIGHLIGHTS• The RNA-binding protein TARBP2 controls the stability of its target transcripts in the nucleus• Nuclear TARBP2 recruits the methyltransferase complex to deposit m 6 A marks on its target transcripts • TARBP2 and m 6 A-mediated interactions with splicing and nuclear RNA surveillance complexes result in target transcript intron retention and decay.• Increased TARBP2 expression is associated with lung cancer and promotes lung cancer growth in vivo.• The transcription factor ZNF143 drives oncogenic TARBP2 upregulation in lung cancer.

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RNA fate determination through cotranscriptional adenosine methylation and microprocessor binding

Cited by 130 publications

References 63 publications

RNA m6A modification and its function in diseases

RNA m6A modification and its function in diseases

Intragenic Enhancers Attenuate Host Gene Expression

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

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