| First Author | Ishikura S | Year | 2016 |
| Journal | Biochim Biophys Acta | Volume | 1859 |
| Issue | 11 | Pages | 1398-1410 |
| PubMed ID | 27591365 | Mgi Jnum | J:251361 |
| Mgi Id | MGI:6106301 | Doi | 10.1016/j.bbagrm.2016.08.010 |
| Citation | Ishikura S, et al. (2016) Molecular mechanisms of transcriptional regulation by the nuclear zinc-finger protein Zfat in T cells. Biochim Biophys Acta 1859(11):1398-1410 |
| abstractText | Zfat is a nuclear protein with AT-hook and zinc-finger domains. We previously reported that Zfat plays crucial roles in T-cell survival and development in mice. However, the molecular mechanisms whereby Zfat regulates gene expression in T cells remain unexplored. In this study, we analyzed the genome-wide occupancy of Zfat by chromatin immunoprecipitation with sequencing (ChIP-seq), which showed that Zfat bound predominantly to a region around a transcription start site (TSS), and that an 8-bp nucleotide sequence GAA(T/A)(C/G)TGC was identified as a consensus sequence for Zfat-binding sites. Furthermore, about half of the Zfat-binding sites were characterized by histone H3 acetylations at lysine 9 and lysine 27 (H3K9ac/K27ac). Notably, Zfat gene deletion decreased the H3K9ac/K27ac levels at the Zfat-binding sites, suggesting that Zfat may be related to the regulation of H3K9ac/K27ac. Integrated analysis of ChIP-seq and transcriptional profiling in thymocytes identified Zfat-target genes with transcription to be regulated directly by Zfat. We then focused on the chromatin regulator Brpf1, a Zfat-target gene, revealing that Zfat bound directly to a 9-bp nucleotide sequence, CGAANGTGC, which is conserved among mammalian Brpf1 promoters. Furthermore, retrovirus-mediated re-expression of Zfat in Zfat-deficient peripheral T cells restored Brpf1 expression to normal levels, and shRNA-mediated Brpf1 knockdown in peripheral T cells increased the proportion of apoptotic cells, suggesting that Zfat-regulated Brpf1 expression was important for T-cell survival. Our findings demonstrated that Zfat regulates the transcription of target genes by binding directly to the TSS proximal region, and that Zfat-target genes play important roles in T-cell homeostasis. |
