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PLoS Genet 2017 Jan 19;131:e1006538. doi: 10.1371/journal.pgen.1006538.
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Rfx2 Stabilizes Foxj1 Binding at Chromatin Loops to Enable Multiciliated Cell Gene Expression.

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.

PubMed ID: 28103240
PMC ID: PMC5245798
Article link: PLoS Genet
Grant support: [+]

Species referenced: Xenopus
Genes referenced: avd cfap52 ctcf dnai1 e2f4 foxi1 foxj1 foxj1.2 hdx mcc mcidas myb notch1 rfx2 tuba4b tubb2b
Antibodies: Acetylated H3f3a Ab20 FLAG Ab3 GFP Ab5 Methyl H3f3a Ab19 Rad21 Ab1
Morpholinos: rfx2 MO1

GEO Series: GSE76342: Xenbase,  NCBI
GSE76363: NCBI
GSE78176: Xenbase,  NCBI

Article Images: [+] show captions
References [+] :
Aftab, Identification and characterization of novel human tissue-specific RFX transcription factors. 2008, Pubmed