Abstract
Chromatin structure and its alteration play critical roles in the regulation of transcription. However, the transcriptional silencing mechanism with regard to the chromatin structure at an unstimulated state of the interferon (IFN)-stimulated gene (ISG) remains unclear. Here we investigated the role of template activating factor-I (TAF-I, also known as SET) in ISG transcription. Knockdown (KD) of TAF-I increased ISG transcript and simultaneously reduced the histone H1 level on the ISG promoters during the early stages of transcription after IFN stimulation from the unstimulated state. The transcription factor levels on the ISG promoters were increased in TAF-I KD cells only during the early stages of transcription. Furthermore, histone H1 KD also increased ISG transcript. TAF-I and histone H1 double KD did not show the additive effect in ISG transcription, suggesting that TAF-I and histone H1 may act on the same regulatory pathway to control ISG transcription. In addition, TAF-I KD and histone H1 KD affected the chromatin structure near the ISG promoters. On the basis of these findings, we propose that TAF-I and its target histone H1 are key regulators of the chromatin structure at the ISG promoter to maintain the silent state of ISG transcription.
Highlights
Transcriptional regulation is accomplished mainly by the regulatory elements such as promoters and enhancers, those of which have a variety of binding sites for sequence-specific transcription factors, and specify characteristic chromatin structures mediated by nucleosome positioning, specific histone modifications, histone variants and other factors [1,2]
The messenger ribonucleic acid (mRNA) levels of the other ISGs showed similar effects in a time-dependent manner (Supplementary Figure S1C). These results indicate that TAF-I negatively regulates ISG transcription and suggest that TAF-I could be involved in the maintenance of the transcriptionally silent state of ISGs
The amount of residual genomic deoxyribonucleic acid (DNA) from the micrococcal nuclease (MNase) digestion was significantly reduced in TAF-I and histone H1 KD cells compared to control cells in the transcriptionally silent state and during the early stage of transcription induced by IFN stimulation (Figure 5B and Supplementary Figure S4)
Summary
Transcriptional regulation is accomplished mainly by the regulatory elements such as promoters and enhancers, those of which have a variety of binding sites for sequence-specific transcription factors, and specify characteristic chromatin structures mediated by nucleosome positioning, specific histone modifications, histone variants and other factors [1,2]. For the transcription of type-I interferon (IFN)-stimulated genes (ISGs), ISG promoters containing sequence motifs, known as IFN-stimulated response element (ISRE), are the binding sites of the sequence-specific transcription factors activated by IFN stimulation. The chromatin structure and histone modification around ISRE are regulated by coactivators for ISG transcription [3,4]. BRG1, an adenosine triphosphate (ATP)-dependent nucleosome remodeling factor and a subunit of the SWI/SNF complex, interacts with STAT2 in response to IFN, facilitates the chromatin remodeling of the ISG promoter region and promotes ISG transcription [13,14,15]. BAF200, a subunit of the SWI/SNF complex, has been found to be required for selective ISG transcription [16] These studies suggest that ISG transcription via ISG promoters is under the control of the combined effects of histone modification and specific chromatin structures. It is unclear as to how the chromatin structure of ISG promoters is regulated to be in the unstimulated state, namely the transcriptionally silent state, in the absence
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