The chromatin-remodeling enzyme BRG1 coordinates CIITA induction through many interdependent distal enhancers.
The chromatin-remodeling enzyme BRG1 is critical for interferon-gamma (IFN-gamma)-mediated gene induction. Promoter-proximal elements are sufficient to mediate BRG1 dependency at some IFN-gamma targets. In contrast, we show here that at CIITA, which encodes the 'master regulator' of induction of major histocompatibility complex class II, distal elements conferred BRG1 dependency. At the uninduced locus, many sites formed BRG1-independent loops. One loop juxtaposed a far downstream element adjacent to a far upstream site. Notably, BRG1 was recruited to the latter site, which triggered the appearance of a histone 'mark' linked to activation. This subtle change was crucial, as subsequent IFN-gamma-induced recruitment of the transcription factors STAT1, IRF1 and p300, as well as histone modifications, accessibility and additional loops, showed BRG1 dependency. Like BRG1, each remote element was critical for the induction of CIITA expression. Thus, BRG1 regulates CIITA through many interdependent remote enhancers, not through the promoter alone.
Ni
Zuyao
Z
Genetics and Development Division, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada.
Abou El Hassan
Mohamed
M
Xu
Zhaodong
Z
Yu
Tao
T
Bremner
Rod
R
D002843:Chromatin / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D015870:Gene Expression; D005786:Gene Expression Regulation; D005809:Genes, Regulator / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation
D002843:Chromatin; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D007371:Interferon-gamma; C084108:SMARCA4 protein, human; D004265:DNA Helicases