a model for how signal duration can determine distinct outcomes of gene transcription programs模型信号持续时间如何确定不同的基因转录程序的结果.pdfVIP

A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs 1 5 1,2,3,4 Kevin D. Fowler , Vijay K. Kuchroo , Arup K. Chakraborty * 1 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 2 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 3 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 4 Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, United States of America, 5 Center for Neurologic Diseases, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America Abstract The reason why IL-6 induces a pro-inflammatory response, while IL-10 induces an anti-inflammatory response, despite both cytokines activating the same transcription factor, STAT3, is not well understood. It is known that IL-6 induces a transient STAT3 signal and that IL-10 induces a sustained STAT3 signal due to the STAT3-induced inhibitor SOCS3’s ability to bind to the IL-6R and not the IL-10R. We sought to develop a general transcriptional network that is capable of translating sustained signals into one response, while translating transient signals into a second response. The general structure of such a network is that the transcription factor STAT3 can induce both an inflammatory response and an anti-inflammatory response by inducing two different genes. The anti-inflammatory gene can bind to and inhibit the inflammatory gene’s production and the inflammatory gene can bind to its own promoter and induce its own transcription in the absence of the