Rfx2 stabilizes Foxj1 binding at chromatin loops to enable multiciliated cell gene expression
| Autor: | Chris Kintner, Ian K. Quigley |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Xenopus Gene Expression Xenopus Proteins Biochemistry Database and Informatics Methods 0302 clinical medicine Gene expression Promoter Regions Genetic Genetics (clinical) Skin Genetics 0303 health sciences Chromosome Biology Forkhead Transcription Factors Animal Models Chromatin Cell biology Experimental Organism Systems Vertebrates Motile cilium Frogs Epigenetics Cellular Structures and Organelles Sequence Analysis Research Article Protein Binding Transcriptional Activation lcsh:QH426-470 Bioinformatics DNA transcription Regulatory Factor X Transcription Factors Biology Research and Analysis Methods Amphibians 03 medical and health sciences Forkhead Box Model Organisms Protein Domains Species Specificity Sequence Motif Analysis DNA-binding proteins Animals Gene Regulation Cilia Enhancer Molecular Biology Transcription factor Gene Ecology Evolution Behavior and Systematics ChIA-PET Locus control region 030304 developmental biology Organisms Biology and Life Sciences Proteins Promoter Cell Biology Regulatory Proteins lcsh:Genetics 030104 developmental biology RFX2 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 13, Iss 1, p e1006538 (2017) |
| Popis: | Cooperative transcription factor binding at cis-regulatory sites in the genome drives robust eukaryotic gene expression, and many such sites must be coordinated to produce coherent transcriptional programs. The transcriptional program leading to motile cilia formation requires members of the DNA-binding forkhead (Fox) and Rfx transcription factor families and these factors co-localize to cilia gene promoters, but it is not clear how many cilia genes are regulated by these two factors, whether these factors act directly or indirectly, or how these factors act with specificity in the context of a 3-dimensional genome. Here, we use genome-wide approaches to show that cilia genes reside at the boundaries of topological domains and that these areas have low enhancer density. We show that the transcription factors Foxj1 and Rfx2 binding occurs in the promoters of more cilia genes than other known cilia transcription factors and that while Rfx2 binds directly to promoters and enhancers equally, Foxj1 prefers direct binding to enhancers and is stabilized at promoters by Rfx2. Finally, we show that Rfx2 and Foxj1 lie at the anchor endpoints of chromatin loops, suggesting that target genes are activated when Foxj1 bound at distal sites is recruited via a loop created by Rfx2 binding at both sites. We speculate that the primary function of Rfx2 is to stabilize distal enhancers with proximal promoters by operating as a scaffolding factor, bringing key regulatory domains bound by Foxj1 into close physical proximity and enabling coordinated cilia gene expression. Author Summary The multiciliated cell extends hundreds of motile cilia to produce fluid flow in the airways and other organ systems. The formation of this specialized cell type requires the coordinated expression of hundreds of genes in order to produce all the protein parts motile cilia require. While a relatively small number of transcription factors has been identified that promote gene expression during multiciliate cell differentiation, it is not clear how they work together to coordinate the expression of genes required for multiple motile ciliation. Here, we show that two transcription factors known to drive cilia formation, Foxj1 and Rfx2, play complementary roles wherein Foxj1 activates target genes but tends not to bind near them in the genome, whereas Rfx2 can’t activate target genes by itself but instead acts as a scaffold by localizing Foxj1 to the proper targets. These results suggest not only a mechanism by which complex gene expression is coordinated in multiciliated cells, but also how transcriptional programs in general could be modular and deployed across different cellular contexts with the same basic promoter configuration. |
| Databáze: | OpenAIRE |
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