Structural basis of INTAC-regulated transcription

Zheng, Huirong; Jin, Qianwei; Wang, Xinxin; Qi, Ying; Liu, Weida; Ren, Yulei; Zhao, Decai; Chen, Fei Xavier; Cheng, Jingdong; Chen, Xizi; Xu, Yanhui

doi:10.1093/procel/pwad010

Cited by 23 publications

(31 citation statements)

References 15 publications

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“…High anisotropy of the reconstruction does not allow for accurate side-chain modelling, therefore the map was only used after low-pass filtering for fitting in secondary structure elements (Figure S4). The best-defined region of the cryo-EM map is centred around INTS5/8 (Figure 2A), which remains unchanged when compared to previously reported structures of the Integrator-PP2A 20 and Integrator-PEC complexes 44,45 expected to abolish this interaction and analysed their effects in vitro and in vivo. First, we transiently expressed INTS15 and its variants in HEK293T cells, purified them using hemagglutinin (HA)-agarose resin and subjected them to TMT-plex differential quantitative proteomics (Figure 2D).…”

Section: Interaction Of the Arm Module With The Core Of The Integrato...mentioning

confidence: 72%

Structural basis of the Integrator complex assembly and association with transcription factors

Razew,

Fraudeau,

Pfleiderer

et al. 2024

Preprint

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SummaryIntegrator is a multi-subunit protein complex responsible for premature transcription termination of coding and non-coding RNAs in Metazoans. This is achieved via Integrator’s two enzymatic activities, RNA endonuclease and protein phosphatase, acting on the promoter-proximally paused RNA Polymerase II (RNAPII). Yet, it remains unclear how Integrator assembly and recruitment are regulated and what are the functions of many of its core subunits. Here we report two cryo-EM reconstructions of large Integrator sub-complexes: INTS10/13/14/15 (Arm module) and INTS5/8/10/15, which allowed integrative modelling of the fully-assembled Integrator bound to the RNAPII paused elongating complex (PEC). INTS13/14 are positioned near the DNA upstream from the transcription pause site, suggesting a potential role in the chromatin context. Anin silicoprotein interaction screen of over 1500 transcription factors (TFs), identified Zinc Finger Protein 655 (ZNF655) as a direct interacting partner of INTS13 that associates with a fully assembled, 17-subunit Integrator complex. We propose a model wherein the Arm module acts as a platform for the recruitment of TFs that could modulate the stability of the Integrator’s association at specific loci and modulate transcription attenuation of the target genes.

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Section: Interaction Of the Arm Module With The Core Of The Integrato...mentioning

confidence: 72%

Structural basis of the Integrator complex assembly and association with transcription factors

Razew,

Fraudeau,

Pfleiderer

et al. 2024

Preprint

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show abstract

“…None of the published structures of INT, neither in isolation nor bound to PEC, contain all INTS and in particular the whole ITFM is missing. 13,16,30 Therefore, we used a combination of biochemical mapping, AF2 predictions and reanalysis of published cryoEM maps to further complete the INT structure.…”

Section: Ints15 and Dss1 Are Stable Subunits Of Intmentioning

confidence: 99%

“…[9][10][11] These phosphorylations lead to NELF dissociation, transformation of DSIF into an elongation factor, and recruitment of elongation complexes to RNAP2. 12 Alternatively, paused RNAP2 (paused-elongation complex, PEC) can also be bound by the Integrator complex (INT), [13][14][15][16] which cleaves the nascent transcript, and keeps NELF, DSIF and RNAP2's CTD in a dephosphorylated state, thereby counteracting elongation and instead eliciting premature transcription termination. 17 Thus, INT acts as a repressor of full length mRNA transcription in a process that has been termed attenuation.…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic basis of gene-specific transcription regulation by the Integrator complex

Sabath,

Nabih,

Arnold

et al. 2024

Preprint

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The Integrator complex (INT) regulates gene expression via premature transcription termination of RNA polymerase II (RNAP2) at promoter-proximal pausing sites. This attenuation of transcription is required for cellular response to external stimuli, cell differentiation and neurodevelopment. How gene-specific regulation is achieved by INT in an inducible manner remains unclear. Here, we identify two sites on INT subunits 13/14 that serve as direct binding hubs for diverse sets of sequence-specific transcription factors (TFs) and other transcription effector complexes. The TFs co-localize with INT genome-wide, increase INT abundance on target genes and co-regulate inducible transcriptional programs. Consistently, disruption of INT-TF contacts impairs sensory cilia formation in response to glucose starvation. Structural analysis places INT's TF binding hubs upstream of the transcription bubble when attached to paused RNAP2, consistent with simultaneous TF-promoter association. Our data establish TF-mediated recruitment of INT to promoters as a widespread mechanism for targeted and inducible transcription attenuation.

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“…Existing methods for the delayed feedback problem can be classified into two types based on the problem setting: online training [3,4,7,10,11,24,25,31] and offline training [2,16,27,28]. In the online setting, when new user behaviors are logged, the model is immediately updated on the new data to keep it fresh.…”

Section: Introductionmentioning

confidence: 99%

Unbiased Delayed Feedback Label Correction for Conversion Rate Prediction

Wang

Sun

Zhou

et al. 2023

Proceedings of the 29th ACM SIGKDD Conference on Knowledge Discovery and Data Mining

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Conversion rate prediction is critical to many online applications such as digital display advertising. To capture dynamic data distribution, industrial systems often require retraining models on recent data daily or weekly. However, the delay of conversion behavior usually leads to incorrect labeling, which is called delayed feedback problem. Existing work may fail to introduce the correct information about false negative samples due to data sparsity and dynamic data distribution. To directly introduce the correct feedback label information, we propose an Unbiased delayed feedback Label Correction framework (ULC), which uses an auxiliary model to correct labels for observed negative feedback samples. Firstly, we theoretically prove that the label-corrected loss is an unbiased estimate of the oracle loss using true labels. Then, as there are no ready training data for label correction, counterfactual labeling is used to construct artificial training data. Furthermore, since counterfactual labeling utilizes only partial training data, we design an embedding-based alternative training method to enhance performance. Comparative experiments on both public and private datasets and detailed analyses show that our proposed approach effectively alleviates the delayed feedback problem and consistently outperforms the previous state-of-the-art methods.

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Structural basis of INTAC-regulated transcription

Cited by 23 publications

References 15 publications

Structural basis of the Integrator complex assembly and association with transcription factors

Structural basis of the Integrator complex assembly and association with transcription factors

Mechanistic basis of gene-specific transcription regulation by the Integrator complex

Unbiased Delayed Feedback Label Correction for Conversion Rate Prediction

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