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      Coordinated regulation of RNA polymerase II pausing and elongation progression by PAF1

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          Abstract

          Pleiotropic transcription regulator RNA polymerase II (Pol II)–associated factor 1 (PAF1) governs multiple transcriptional steps and the deposition of several epigenetic marks. However, it remains unclear how ultimate transcriptional outcome is determined by PAF1 and whether it relates to PAF1-controlled epigenetic marks. We use rapid degradation systems and reveal direct PAF1 functions in governing pausing partially by recruiting Integrator-PP2A (INTAC), in addition to ensuring elongation. Following acute PAF1 degradation, most destabilized polymerase undergoes effective release, which presumably relies on skewed balance between INTAC and P-TEFb, resulting in hyperphosphorylated substrates including SPT5. Impaired Pol II progression during elongation, along with altered pause release frequency, determines the final transcriptional outputs. Moreover, PAF1 degradation causes a cumulative decline in histone modifications. These epigenetic alterations in chromatin likely further influence the production of transcripts from PAF1 target genes.

          Abstract

          PAF1 determines gene expression by coordinating the regulation of INTAC recruitment, Pol II pausing, and elongation.

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          Most cited references85

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          Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

          Michael Love, Wolfgang Huber, Simon Anders (2014)
          In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0550-8) contains supplementary material, which is available to authorized users.
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            The Sequence Alignment/Map format and SAMtools

            Heng Li, Bob Handsaker, Alec Wysoker … (2009)
            Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
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              Fast gapped-read alignment with Bowtie 2.

              Ben Langmead, Steven L Salzberg (2022)
              As the rate of sequencing increases, greater throughput is demanded from read aligners. The full-text minute index is often used to make alignment very fast and memory-efficient, but the approach is ill-suited to finding longer, gapped alignments. Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.
              Article 0 comments Cited 13008 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Zhenning Wang:
                ORCID: https://orcid.org/0000-0002-0391-1534
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - review & editing
                Aixia Song:
                ORCID: https://orcid.org/0000-0003-2300-9238
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Hao Xu:
                ORCID: https://orcid.org/0000-0002-2742-8715
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draft
                Shibin Hu:
                ORCID: https://orcid.org/0000-0003-1780-3443
                Role: InvestigationRole: MethodologyRole: Project administrationRole: Validation
                Bolin Tao: Role: InvestigationRole: ValidationRole: VisualizationRole: Writing - review & editing
                Linna Peng:
                ORCID: https://orcid.org/0000-0002-4094-8002
                Role: Data curationRole: Formal analysisRole: ResourcesRole: Software
                Jingwen Wang:
                ORCID: https://orcid.org/0000-0001-6716-4614
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Jiabei Li:
                ORCID: https://orcid.org/0000-0002-0071-6792
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Jiali Yu:
                ORCID: https://orcid.org/0000-0001-9302-077X
                Role: Validation
                Li Wang: Role: Investigation
                Ze Li:
                ORCID: https://orcid.org/0000-0003-4179-8672
                Role: Resources
                Xizi Chen:
                ORCID: https://orcid.org/0000-0002-4120-104X
                Role: InvestigationRole: Resources
                Mengyun Wang: Role: ConceptualizationRole: Formal analysisRole: Methodology
                Yayun Chi: Role: InvestigationRole: Validation
                Jiong Wu:
                ORCID: https://orcid.org/0000-0002-8103-0505
                Role: Formal analysisRole: Validation
                Yanhui Xu:
                ORCID: https://orcid.org/0000-0002-1408-5178
                Role: ConceptualizationRole: Supervision
                Hai Zheng:
                ORCID: https://orcid.org/0000-0002-8460-6610
                Role: InvestigationRole: SupervisionRole: VisualizationRole: Writing - original draft
                Fei Xavier Chen:
                ORCID: https://orcid.org/0000-0002-7827-7988
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Journal
                Journal ID (nlm-ta): Sci Adv
                Journal ID (iso-abbrev): Sci Adv
                Journal ID (publisher-id): sciadv
                Journal ID (hwp): advances
                Title: Science Advances
                Publisher: American Association for the Advancement of Science
                ISSN (Electronic): 2375-2548
                Publication date Collection: April 2022
                Publication date (Electronic, pub): 01 April 2022
                Volume: 8
                Issue: 13
                Electronic Location Identifier: eabm5504
                Affiliations
                [1 ]Fudan University Shanghai Cancer Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
                [2 ]Shanghai Key Laboratory of Radiation Oncology, Shanghai, China.
                [3 ]Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
                Author notes
                [* ]Corresponding author. Email: feixchen@ 123456fudan.edu.cn
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-0391-1534
                https://orcid.org/0000-0003-2300-9238
                https://orcid.org/0000-0002-2742-8715
                https://orcid.org/0000-0003-1780-3443
                https://orcid.org/0000-0002-4094-8002
                https://orcid.org/0000-0001-6716-4614
                https://orcid.org/0000-0002-0071-6792
                https://orcid.org/0000-0001-9302-077X
                https://orcid.org/0000-0003-4179-8672
                https://orcid.org/0000-0002-4120-104X
                https://orcid.org/0000-0002-8103-0505
                https://orcid.org/0000-0002-1408-5178
                https://orcid.org/0000-0002-8460-6610
                https://orcid.org/0000-0002-7827-7988
                Article
                Publisher ID: abm5504
                DOI: 10.1126/sciadv.abm5504
                PMC ID: 11093130
                PubMed ID: 35363521
                SO-VID: 2c840629-6a33-4e5c-9de6-17a62a4e91d9
                Copyright © Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                Date received : 25 September 2021
                Date accepted : 11 February 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100007219, Natural Science Foundation of Shanghai;
                Award ID: 20ZR1412100
                Funded by: FundRef http://dx.doi.org/10.13039/100007219, Natural Science Foundation of Shanghai;
                Award ID: 22ZR1412400
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 32070636
                Funded by: National key R&D program of China;
                Award ID: 2021YFA1301700
                Categories
                Subject: Research Article
                Subject: Biomedicine and Life Sciences
                Subject: SciAdv r-articles
                Subject: Biochemistry
                Subject: Molecular Biology
                Subject: Molecular Biology
                Custom metadata
                Copyeditor Vivian Hernandez

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