Asada Ryuta, Umeda Miki, Adachi Akira, Senmatsu Satoshi, Abe Takuya, Iwasaki Hiroshi, Ohta Kunihiro, Hoffman Charles S, Hirota Kouji
Department of Chemistry, Graduate School of Science and Engineering, Tokyo Metropolitan University, Minamiosawa 1-1, Hachioji-shi, Tokyo 192-0397, Japan.
Cell Biology Unit, Institute of Innovative Research, Tokyo Institute of Technology M6-11, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8550, Japan.
Nucleic Acids Res. 2017 Sep 19;45(16):9361-9371. doi: 10.1093/nar/gkx555.
Transcription factors (TFs) determine the transcription activity of target genes and play a central role in controlling the transcription in response to various environmental stresses. Three dimensional genome structures such as local loops play a fundamental role in the regulation of transcription, although the link between such structures and the regulation of TF binding to cis-regulatory elements remains to be elucidated. Here, we show that during transcriptional activation of the fission yeast fbp1 gene, binding of Rst2 (a critical C2H2 zinc-finger TF) is mediated by a local loop structure. During fbp1 activation, Rst2 is first recruited to upstream-activating sequence 1 (UAS1), then it subsequently binds to UAS2 (a critical cis-regulatory site located approximately 600 base pairs downstream of UAS1) through a loop structure that brings UAS1 and UAS2 into spatially close proximity. Tup11/12 (the Tup-family corepressors) suppress direct binding of Rst2 to UAS2, but this suppression is counteracted by the recruitment of Rst2 at UAS1 and following delivery to UAS2 through a loop structure. These data demonstrate a previously unappreciated mechanism for the recruitment and expansion of TF-DNA interactions within a promoter mediated by local three-dimensional genome structures and for timely TF-binding via counteractive regulation by the Tup-family corepressors.
转录因子（TFs）决定靶基因的转录活性，并在响应各种环境胁迫时控制转录过程中发挥核心作用。诸如局部环等三维基因组结构在转录调控中起着基础性作用，尽管此类结构与TF与顺式调控元件结合的调控之间的联系仍有待阐明。在此，我们表明在裂殖酵母fbp1基因的转录激活过程中，Rst2（一种关键的C2H2锌指TF）的结合是由局部环结构介导的。在fbp1激活过程中，Rst2首先被招募到上游激活序列1（UAS1），然后它通过一种环结构与UAS2（位于UAS1下游约600个碱基对处的关键顺式调控位点）结合，该环结构使UAS1和UAS2在空间上紧密靠近。Tup11/12（Tup家族共抑制因子）抑制Rst2与UAS2的直接结合，但这种抑制作用会被Rst2在UAS1处的招募以及随后通过环结构传递到UAS2所抵消。这些数据证明了一种以前未被认识到的机制，即通过局部三维基因组结构介导启动子内TF-DNA相互作用的招募和扩展，以及通过Tup家族共抑制因子的反式调控实现TF的适时结合。
