转录共激活因子CRTC2通过相分离调控转录延伸的机制研究

转录延伸是当前基因表达调控研究的前沿和热点。P-TEFb激酶是最为重要的转录延伸调控复合体，但其如何响应外界信号刺激，进而特异性地激活下游靶基因的转录延伸的分子机制仍有待阐明。我们前期结果表明，cAMP信号可通过激活P-TEFb激酶促进转录延伸和靶基因表达。CRTC2是cAMP通路的重要转录共激活因子。我们发现，CRTC2可以直接和P-TEFb相互作用，并依赖P-TEFb激活下游靶基因。最新研究表明，P-TEFb可通过相分离方式调控转录延伸。我们发现，CRTC2在体内体外也可发生相分离。拟开展的工作将进一步探讨相分离在调节CRTC2与P-TEFb二者之间相互作用、调控P-TEFb激酶活化、转录延伸及下游靶基因表达中的功能和机制。这一研究将有助于我们理解cAMP-CRTC2信号通路调控基因表达的分子机制，理解P-TEFb介导的转录延伸对外界信号的响应以及相变在转录调控中的作用。

Transcription elongation is emerging as the major regulator step in gene expression. P-TEFb kinase complex is the most important regulator of transcription elongation. However, the mechanisms underlying signal-regulated P-TEFb activation and gene specific transcription elongation regulation remain largely unknown. We have previously reported that cAMP signaling activates P-TEFb kinase to promote transcription elongation and target gene expression. Accumulating evidence indicates that CRTC2 plays critical roles in the activation of cAMP downstream target genes. Our preliminary data showed that CRTC2 interacts with P-TEFb upon activation of cAMP signaling. Luciferase reporter assays revealed that the trans-activity of CRTC2 depended on P-TEFb kinase activity. Recently studies reported that P-TEFb promoted transcription elongation via a phase-separation mechanism. We found that CRTC2 formed liquid-like condensates in vitro and in vivo. The future work will focus on investigating the role of phase separation in regulating the interaction between CRTC2 and P-TEFb, in controlling P-TEFb kinase activity, in promoting transcription elongation and downstream target gene expression. This study will help us understand the molecular mechanisms of cAMP-CRTC2 signaling-induced genes expression, the response of P-TEFb-mediated transcription elongation on external signals and the role of phase separation in transcriptional regulation.