A combinatorial view of old and new RNA polymerase II modifications

Lyons, Danielle E; McMahon, Sarah; Ott, Melanie

doi:10.1080/21541264.2020.1762468

Cited by 15 publications

(10 citation statements)

References 202 publications

(275 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To further validate this finding, we performed ChIP-seq analysis using antibodies against RNAPII Ser5, a modification status associated with transcription initiation/elongation (Hsin & Manley, 2012; Lyons et al , 2020). Consistent with the finding from previous studies that RNAPII Ser5 has major binding peak at TSS, our results revealed similar patterns in hESCs.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, we combined these observations with the aforementioned data in which CFIm25 overexpression rescued the gene expression phenotype, and concluded that CFIm25 may be directly responsible for the observed transcription effect. To further validate this finding, we performed ChIP-seq analysis using antibodies against RNAPII Ser5, a modification status associated with transcription initiation/elongation (Hsin & Manley, 2012;Lyons et al, 2020).…”

Section: Cfim25 Significantly Affects Gene Transcription Dynamics In Hescsmentioning

confidence: 99%

See 1 more Smart Citation

CFIm25 regulates human stem cell function independently of its role in mRNA alternative polyadenylation

Yao

Huang

et al. 2021

Preprint

View full text Add to dashboard Cite

It has recently been shown that CFIm25, a canonical mRNA 3’ processing factor, could play a variety of physiological roles through its molecular function in the regulation of mRNA alternative polyadenylation (APA). Here, we used CRISPR/Cas9-mediated gene editing approach in human embryonic stem cells (hESCs) for CFIm25, and obtained three gene knockdown/mutant cell lines. CFIm25 gene editing resulted in higher proliferation rate and impaired differentiation potential for hESCs, with these effects likely to be directly regulated by the target genes, including the pluripotency factor rex1. Mechanistically, we unexpected found that perturbation in CFIm25 gene expression did not significantly affect cellular mRNA 3’ processing efficiency and APA profile. Rather, we provided evidences that CFIm25 may impact RNA polymerase II (RNAPII) occupancy at the body of transcribed genes, and promote the expression level of a group of transcripts associated with cellular proliferation and/or differentiation. Further study indicated that CFIm25 association with LEO1, an RNAPII associated factor, might contribute to the effect. Taken together, these results reveal novel mechanisms underlying CFIm25’s modulation in determination of cell fate, and provide evidence that the process of mammalian gene transcription may be regulated by an mRNA 3’ processing factor.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Cfim25 Significantly Affects Gene Transcription Dynamics In Hescsmentioning

confidence: 99%

CFIm25 regulates human stem cell function independently of its role in mRNA alternative polyadenylation

Yao

Huang

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…CDK7, CDK8, CDK9, CDK12 and CDK13) regulate transcription by modulating the phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II (RNAPOLII). [12][13][14][15][16][17][18] The CDK family can be harnessed to regulate oncogene activity.…”

Section: Introductionmentioning

confidence: 99%

The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super‐enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis‐generating study

Huang,

Yang,

Chen

et al. 2023

Clinical & Translational Med

View full text Add to dashboard Cite

BackgroundInhibition of CDK7, a potent transcription regulator, may bring new hope for treating pancreatic ductal adenocarcinoma (PDAC), which is featured by large genetic heterogeneity and abundant KRAS mutations. This investigation aimed at exploring the discrepant efficacies of THZ1, a small‐molecule covalent CDK7 inhibitor, on PDACs with different KRAS mutations and the underlying mechanisms.MethodsAssociations of CDK7 expression with survival by KRAS mutations were first assessed. Effects of THZ1 on PDAC by different KRAS mutations were then investigated in vitro and in vivo. Moreover, the effects of THZ1 on gene transcription and phosphorylation of RNA polymerase II (RNAPOLII) in different KRAS mutant PDACs were assessed, and the effect of THZ1 on super‐enhancer activity was evaluated using chromatin immunoprecipitation sequencing. Lastly, the effects of THZ1 on the binding of H3K27ac to PIK3CA and on the PI3K/AKT/mTOR signalling were analysed.ResultsHigh CDK7 expression was significantly linked to worse survival within PDAC patients carrying KRAS‐G12V mutation but not in those with KRAS‐G12D mutation. The apoptosis‐inducing effect of THZ1 was markedly stronger in KRAS‐G12V PDAC than KRAS‐G12D cancer. THZ1 significantly inhibited the growth of xenograft tumour with KRAS‐G12V mutation, and the inhibition was markedly stronger than for KRAS‐G12D tumour. In mini‐cell‐derived xenograft (CDX) models, THZ1 significantly suppressed KRAS‐G12V PDAC but not KRAS‐G12D cancer. THZ1 significantly suppressed the phosphorylation of RNAPOLII, and this effect was stronger in KRAS‐G12V PDAC (especially at ser5). KRAS‐G12V PDAC had more H3K27ac‐binding super‐enhancers, and the inhibition of THZ1 on super‐enhancer activity was also stronger in KRAS‐G12V PDAC. Furthermore, THZ1 significantly weakened the binding of H3K27ac to PIK3CA in KRAS‐G12V PDAC. THZ1 significantly suppressed the PI3K/AKT/mTOR pathway and its downstream markers, and this effect was stronger in KRAS‐G12V cells.ConclusionsIn this hypothesis‐generating study, THZ1 might selectively inhibit certain PDACs with KRAS‐G12V mutation more potently compared with some other PDACs with KRAS‐G12D mutation, which might be associated with its effect on super‐enhancer activity and the PI3K/AKT/mTOR signalling. Our findings might offer novel key clues for the precise management of PDAC and important evidence for future targeted trial design.Highlights THZ1 had a stronger effect on PDAC‐bearing KRAS‐G12V mutation than G12D mutation. Suppressive effect of THZ1 on phosphorylation of RNAPOLII was stronger in KRAS‐G12V than KRAS‐G12D PDAC. Inhibition of THZ1 on super‐enhancer activity and H3K27ac binding to PIK3CA was stronger in KRAS‐G12V PDAC. Suppressive effect of THZ1 on PI3K/AKT/mTOR pathway was stronger in KRAS‐G12V PDAC.

show abstract

“…The CTD is modified within a repetitive conserved heptad sequence (Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7) ( Akhtar et al., 2009 ; Buratowski, 2009 ; Corden, 2013 ; Eick and Geyer, 2013 ; Fabrega et al., 2003 ; Govind et al., 2010 ; Jasnovidova and Stefl, 2013 ; Ng et al., 2003 ; Vasiljeva et al., 2008 ; Zaborowska et al., 2016 ; Zhang et al., 2012 ). CTD phosphorylation on Tyr1, Ser2, Thr4, Ser5, and Ser7 is tightly controlled by various kinases and phosphatases ( Cho et al., 2001 ; Harlen and Churchman, 2017 ; Jeronimo et al., 2016 ; Kecman et al., 2018a ; Lyons et al., 2020 ; Nemec et al., 2019 ; Sanso and Fisher, 2013 ; Tietjen et al., 2010 ; Yurko and Manley, 2018 ), establishing RNAPII phosphorylation states specific to each stage of the transcription cycle (referred to as the “CTD code”). Once unphosphorylated RNAPII binds to the promoter, TFIIH unwinds the downstream DNA to form a transcription bubble and phosphorylates Ser5 on the CTD ( Holstege et al., 1996 ; Kim et al., 2000 ; Komarnitsky et al., 2000 ).…”

Section: Introductionmentioning

confidence: 99%

Transcription and chromatin-based surveillance mechanism controls suppression of cryptic antisense transcription

et al. 2021

View full text Add to dashboard Cite

Phosphorylation of the RNA polymerase II C-terminal domain Y 1 S 2 P 3 T 4 S 5 P 6 S 7 consensus sequence coordinates key events during transcription, and its deregulation leads to defects in transcription and RNA processing. Here, we report that the histone deacetylase activity of the fission yeast Hos2/Set3 complex plays an important role in suppressing cryptic initiation of antisense transcription when RNA polymerase II phosphorylation is dysregulated due to the loss of Ssu72 phosphatase. Interestingly, although single Hos2 and Set3 mutants have little effect, loss of Hos2 or Set3 combined with ssu72D results in a synergistic increase in antisense transcription globally and correlates with elevated sensitivity to genotoxic agents. We demonstrate a key role for the Ssu72/Hos2/Set3 mechanism in the suppression of cryptic antisense transcription at the 3 0 end of convergent genes that are most susceptible to these defects, ensuring the fidelity of gene expression within dense genomes of simple eukaryotes.

show abstract

A combinatorial view of old and new RNA polymerase II modifications

Cited by 15 publications

References 202 publications

CFIm25 regulates human stem cell function independently of its role in mRNA alternative polyadenylation

CFIm25 regulates human stem cell function independently of its role in mRNA alternative polyadenylation

The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super‐enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis‐generating study

Transcription and chromatin-based surveillance mechanism controls suppression of cryptic antisense transcription

Contact Info

Product

Resources

About