Agata Yasutoshi, Tamaki Nobuyuki, Sakamoto Shuji, Ikawa Tomokatsu, Masuda Kyoko, Kawamoto Hiroshi, Murre Cornelis
Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Immunity. 2007 Dec;27(6):871-84. doi: 10.1016/j.immuni.2007.11.015.
Allelic exclusion of antigen-receptor genes is ensured primarily by monoallelic locus activation upon rearrangement and subsequently by feedback inhibition of continued rearrangement. Here, we demonstrated that the basic helix-loop-helix protein, E47, promoted T cell receptor beta (TCRbeta) gene rearrangement by directly binding to target gene segments to increase chromatin accessibility in a dosage-sensitive manner. Feedback signaling abrogated E47 binding, leading to a decline in accessibility. Conversely, enforced expression of E47 induced TCRbeta gene rearrangement by antagonizing feedback inhibition. Thus, the abundance of E47 is rate limiting in locus activation, and feedback signaling downregulates E47 activity to ensure allelic exclusion.
抗原受体基因的等位基因排斥主要通过重排时的单等位基因座激活以及随后对持续重排的反馈抑制来确保。在此，我们证明碱性螺旋-环-螺旋蛋白E47通过直接结合靶基因片段以剂量敏感的方式增加染色质可及性，从而促进T细胞受体β（TCRβ）基因重排。反馈信号消除了E47的结合，导致可及性下降。相反，E47的强制表达通过拮抗反馈抑制诱导TCRβ基因重排。因此，E47的丰度在基因座激活中起限速作用，并且反馈信号下调E47活性以确保等位基因排斥。
