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Initiation of diverse epigenetic states during nuclear programming of the Drosophila body plan
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Number of Authors: 2
2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 31, 8735-8740 p.Article in journal (Refereed) Published
Abstract [en]

Epigenetic patterns of histone modifications contribute to the maintenance of tissue-specific gene expression. Here, we show that such modifications also accompany the specification of cell identities by the NF-kappa B transcription factor Dorsal in the precellular Drosophila embryo. We provide evidence that the maternal pioneer factor, Zelda, is responsible for establishing poised RNA polymerase at Dorsal target genes before Dorsal-mediated zygotic activation. At the onset of cell specification, Dorsal recruits the CBP/p300 coactivator to the regulatory regions of defined target genes in the presumptive neuroectoderm, resulting in their histone acetylation and transcriptional activation. These genes are inactive in the mesoderm due to transcriptional quenching by the Snail repressor, which precludes recruitment of CBP and prevents histone acetylation. By contrast, inactivation of the same enhancers in the dorsal ectoderm is associated with Polycomb-repressed H3K27me3 chromatin. Thus, the Dorsal morphogen gradient produces three distinct histone signatures including two modes of transcriptional repression, active repression (hypoacetylation), and inactivity (H3K27me3). Whereas histone hypoacetylation is associated with a poised polymerase, H3K27me3 displaces polymerase from chromatin. Our results link different modes of RNA polymerase regulation to separate epigenetic patterns and demonstrate that developmental determinants orchestrate differential chromatin states, providing new insights into the link between epigenetics and developmental patterning.

Place, publisher, year, edition, pages
2016. Vol. 113, no 31, 8735-8740 p.
Keyword [en]
epigenetics, cell specification, Drosophila embryo, Dorsal morphogen, Zelda
National Category
Biological Sciences
Research subject
Developmental Biology
Identifiers
URN: urn:nbn:se:su:diva-133375DOI: 10.1073/pnas.1516450113ISI: 000380586600057PubMedID: 27439862OAI: oai:DiVA.org:su-133375DiVA: diva2:967795
Available from: 2016-09-09 Created: 2016-09-06 Last updated: 2016-10-06Bibliographically approved
In thesis
1. Transcriptional and epigenetic control of gene expression in embryo development
Open this publication in new window or tab >>Transcriptional and epigenetic control of gene expression in embryo development
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows.

We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity.

CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin.

Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome. CBP is regulating Pol II activity of nearly all expressed genes, however, either recruitment or release of Pol II is the rate-limiting step affected by CBP.

Taken together, these results reveal mechanistic insights into cell specification and transcriptional control during development.

 

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2016. 72 p.
Keyword
Epigenetics, Cell specification, Drosophila embryo, Dorsal morphogen, CBP/p300, Gene regulation, Chromatin, Promoter proximal Pol II pausing
National Category
Developmental Biology
Research subject
Developmental Biology
Identifiers
urn:nbn:se:su:diva-134354 (URN)978-91-7649-537-7 (ISBN)978-91-7649-538-4 (ISBN)
Public defence
2016-11-25, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

 

Available from: 2016-11-01 Created: 2016-10-05 Last updated: 2016-10-24Bibliographically approved

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