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CBP Regulates Recruitment and Release of Promoter-Proximal RNA Polymerase II
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Per Stenberg, Computational Life Science Cluster (CLiC))
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2017 (English)In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 68, no 3, p. 491-503.e5Article in journal (Refereed) Published
Abstract [en]

Transcription activation involves RNA polymerase II (Pol II) recruitment and release from the promoter into productive elongation, but how specific chromatin regulators control these steps is unclear. Here, we identify a novel activity of the histone acetyltransferase p300/CREB-binding protein (CBP) in regulating promoter-proximal paused Pol II. We find that Drosophila CBP inhibition results in "dribbling" of Pol II from the pause site to positions further downstream but impedes transcription through the +1 nucleosome genome-wide. Promoters strongly occupied by CBP and GAGA factor have high levels of paused Pol II, a unique chromatin signature, and are highly expressed regardless of cell type. Interestingly, CBP activity is rate limiting for Pol II recruitment to these highly paused promoters through an interaction with TFIIB but for transit into elongation by histone acetylation at other genes. Thus, CBP directly stimulates both Pol II recruitment and the ability to traverse the first nucleosome, thereby promoting transcription of most genes.

Place, publisher, year, edition, pages
2017. Vol. 68, no 3, p. 491-503.e5
Keywords [en]
CBP, Drosophila, GAGA-factor, TFIIB, histone acetyltransferase, p300, polymerase pausing, transcription, trithorax-like
National Category
Biochemistry and Molecular Biology Cell Biology
Research subject
Genetics
Identifiers
URN: urn:nbn:se:umu:diva-141589DOI: 10.1016/j.molcel.2017.09.031ISI: 000414250700005PubMedID: 29056321OAI: oai:DiVA.org:umu-141589DiVA, id: diva2:1155627
Funder
Knut and Alice Wallenberg FoundationAvailable from: 2017-11-08 Created: 2017-11-08 Last updated: 2018-11-14Bibliographically approved
In thesis
1. Regulation of gene expression in fruit flies: how does it start, and will it be remembered?
Open this publication in new window or tab >>Regulation of gene expression in fruit flies: how does it start, and will it be remembered?
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

One of the most distinctive features of eukaryotic chromosomes is the bundling of DNA together with functionally associated RNA and proteins in chromatin. This allows huge amounts of DNA to be packed inside the very tiny space of the nucleus, and alterations in the structure of chromatin enable access to the DNA for transcription (“reading” genes by production of RNA copies). Much of the current knowledge of chromatin structure and regulation comes from studies of Drosophila melanogaster. When the chromatin structure is open the transcription of a gene can start after recruitment of the necessary factors. The main enzyme for gene transcription is Polymerase II (Pol II). For successful gene transcription, Pol II must not only be recruited to the gene’s promoter, but also escape from a pausing state which occurs soon after transcription initiation. CBP/P300 is one of the co-activators involved in transcriptional activation. In the studies this thesis is based upon, my colleagues and I (hereafter we) discovered a new function for CBP in transcription activation. Using high throughput sequencing techniques, we found that CBP directly stimulates recruitment of Pol II to promoters, and facilitates its release from the paused state, enabling progression to the elongation stage of transcription.

For cells to remember their identity following division during development, the transcriptional state of genes must be transmitted. Intensively studied players involved in this memory are the Polycomb group (PcG) proteins, responsible for maintaining the repressed state of important developmental genes. The core members are Polycomb repressive complex 1 and 2 (PRC1 and PRC2), which are recruited in flies through poorly known mechanisms to target genes by so-called Polycomb response elements (PREs). Using Drosophila mutant cell lines, we showed that (in contrast to previous models) some PREs can recruit PRC1 even when PRC2 is absent. We also observed that at many PREs, PRC1 is needed for recruitment of PRC2 and concluded that targeting PRC complexes to PREs is a much more flexible and variable process than previously thought.

Some phenotypic effects of environmental changes can be transferred to subsequent generations. Previous efforts to identify the mechanisms involved have focused on material (mainly, but not only, DNA) transferred through germ cells. However, organisms’ microbiomes are also transferred to the next generation. Thus, to investigate possible contributions of microbiomes to such transfer, we used fruit flies as the microbiomes they inherit can be easily controlled. We altered some parents’ environmental conditions by lowering the temperature, then grew offspring that received microbiomes from cold-treated and control parents in control conditions and compared their transcriptional patterns. Our results suggest that most of the crosstalk between the microbiome and the fly happens in the gut, and that further investigation of this previously unsuspected mode of inheritance is warranted.

Place, publisher, year, edition, pages
Umeå: Umeå University, Department of Molecular Biology, 2018. p. 47
Keywords
Drosophila, epigenetics, transcription, gene regulation, transcription maintenance, CBP, polymerase pausing, Polycomb group proteins, transgenerational inheritance of transcriptional response, gut microbiome
National Category
Bioinformatics and Systems Biology Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-153271 (URN)978-91-7601-973-3 (ISBN)
Public defence
2018-12-07, Astrid Fagreus lecture hall (A103), Sjukhusområdet, byggnader 6A, Umeå, 13:00 (English)
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Available from: 2018-11-16 Created: 2018-11-14 Last updated: 2018-11-15Bibliographically approved

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Zare, AmanStenberg, Per

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