The C-Terminal Domain of RNA Polymerase II Is a Multivalent Targeting Sequence that Supports Drosophila Development with Only Consensus Heptads

Lu, Feiyue; Portz, Bede; Gilmour, David S.

doi:10.1016/j.molcel.2019.01.008

Cited by 53 publications

(43 citation statements)

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“…Similarly, we have proposed that RNA Polymerase II's (RNAPII) affinity for common co-factors or even itself could facilitate enhancer-promoter interactions 18,19 . This model is supported by reports that the C-terminal domain (CTD) of RNAPII specifies active promoter localization through its affinity for other CTDs 20 , as well as the low-complexity domain of Cyclin T1 21 . If correct, these models suggest that transcription may be required for distal enhancer function, challenging the commonplace methodology of using DNase hypersensitive sites (DHSs) and histone marks to identify enhancers.…”

Section: Introductionmentioning

confidence: 81%

Transcription imparts architecture, function, and logic to enhancer units

Tippens

Liang

Leung

et al. 2019

Preprint

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Distal enhancers remain one of the least understood regulatory elements with pivotal roles in development and disease. We used massively parallel reporter assays to perform functional comparisons of two leading enhancer models and find that gene-distal transcription start sites (TSSs) are robust predictors of enhancer activity with higher resolution and specificity than histone modifications. We show that active enhancer units are precisely delineated by active TSSs, validate that these boundaries are sufficient to capture enhancer function, and confirm that core promoter sequences are required for this activity. Finally, we assay pairs of adjacent units and find that their cumulative activity is best predicted by the strongest unit within the pair.Synthetic fusions of enhancer units demonstrate that adjacency imposes winner-takes-all logic, revealing a simple design for a maximum-activity filter of enhancer unit outputs. Together, our results define fundamental enhancer units and a principle of non-cooperativity between adjacent units.

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Section: Introductionmentioning

confidence: 81%

Transcription imparts architecture, function, and logic to enhancer units

Tippens

Liang

Leung

et al. 2019

Preprint

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“…In the future, it will be important to validate these descriptive assessments, for example by determining whether the puncta are sensitive to treatment with hexanediol, a chemical used to disrupt phase-separated condensates, and to see whether they contain important transcriptional regulatory components, such as RNA Pol II or CDK9. This would complement other studies that have shown how the carboxy terminal heptapeptide repeats in RNA Pol II mediate phase separation and are important for transcription elongation (Boehning et al, 2018;Lu et al, 2019;Lu et al, 2018). Furthermore, future work will be required to test whether the molecular mechanisms underlying Yki/YAP/TAZ phase separation, identified primarily using purified proteins and in vitro cell culture systems, are relevant in vivo.…”

Section: Phase Separation Of Yap and Tazmentioning

confidence: 76%

The regulation of Yorkie, YAP and TAZ: new insights into the Hippo pathway

2020

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The Hippo pathway is a highly conserved signalling pathway that regulates multiple biological processes, including organ size control and cell fate. Since its discovery, genetic and biochemical studies have elucidated several key signalling steps important for pathway activation and deactivation. In recent years, technical advances in microscopy and genome modification have allowed new insights into Hippo signalling to be revealed. These studies have highlighted that the nuclear-cytoplasmic shuttling behaviour of the Hippo pathway transcriptional co-activators Yorkie, YAP and TAZ is far more dynamic than previously appreciated, and YAP and TAZ are also regulated by liquid-liquid phase separation. Here, we review our current understanding of Yorkie, YAP and TAZ regulation, with a focus on recent microscopy-based studies.

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“…Improvement in gene synthesis and targeting has nevertheless allowed the precise replacement at the endogenous rpb1 locus of the authentic CTD by variants preserving its natural length in yeast ( 15 , 42 ) and more recently in Drosophila ( 43 ), opening the way for genetic dissection of the requirement of CTD phosphorylation in vivo during growth and development. Unexpectedly, these experiments revealed that budding yeast or fission yeast CTD S2A are fully viable, a phenotype contrasting the lethality resulting from the deletion of most genes coding for 3′-end processors, including Pcf11, proposed to be recruited by the S2P mark.…”

Section: Discussionmentioning

confidence: 99%

RNA polymerase II CTD S2P is dispensable for embryogenesis but mediates exit from developmental diapause in C. elegans

et al. 2020

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Serine 2 phosphorylation (S2P) within the CTD of RNA polymerase II is considered a Cdk9/Cdk12-dependent mark required for 3′-end processing. However, the relevance of CTD S2P in metazoan development is unknown. We show that cdk-12 lesions or a full-length CTD S2A substitution results in an identical phenotype in Caenorhabditis elegans. Embryogenesis occurs in the complete absence of S2P, but the hatched larvae arrest development, mimicking the diapause induced when hatching occurs in the absence of food. Genome-wide analyses indicate that when CTD S2P is inhibited, only a subset of growth-related genes is not properly expressed. These genes correspond to SL2 trans-spliced mRNAs located in position 2 and over within operons. We show that CDK-12 is required for maximal occupancy of cleavage stimulatory factor necessary for SL2 trans-splicing. We propose that CTD S2P functions as a gene-specific signaling mark ensuring the nutritional control of the C. elegans developmental program.

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The C-Terminal Domain of RNA Polymerase II Is a Multivalent Targeting Sequence that Supports Drosophila Development with Only Consensus Heptads

Abstract: Highlights d Consensus heptads are sufficient to support Drosophila development d Too many consensus heptads are deleterious d The wild-type Drosophila CTD alone localizes to sites of active transcription d CTDs with too many consensus heptads tend to localize to extrachromosomal foci

Cited by 53 publications

References 50 publications

Transcription imparts architecture, function, and logic to enhancer units

Transcription imparts architecture, function, and logic to enhancer units

The regulation of Yorkie, YAP and TAZ: new insights into the Hippo pathway

RNA polymerase II CTD S2P is dispensable for embryogenesis but mediates exit from developmental diapause in C. elegans

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