PHF6调控核糖体基因编码区转录沉默的机制研究

Histone reader proteins can bind specific modified chromatin. Then they recruit epigenetic modification enzymes and transcription factors to achieve the purpose of given inhibiting or activating gene transcription. As a reader protein, mutations in PHF6 are closely related to a variety of cancer diseases. Furthermore, PHF6 is known to be a nucleolar protein involved in the regulation of the transcriptional activity of ribosomal genes. This project attempts to investigate the mechanism by which PHF6 inhibits the transcription of ribosomal genes. In particular, it explores the functional mechanism of PHF6 in transcription of the silenced ribosomal coding region and explores the histone modifications it recognizes and analyzes its role in the antisense RNA transcriptome. This project identifies the mechanism that PHF6 through the antisense RNA-mediated H4K20me3 modification to inhibit the transcriptional function of the coding region. It provides a new insight into the mechanism by which PHF6 regulates gene transcription and its role in related diseases.

组蛋白修饰阅读器蛋白能够结合特定修饰的染色质进而招募其他表观遗传修饰酶以及转录因子等来达到特异性地抑制或激活基因转录的目的。作为一个阅读器蛋白，PHF6的突变与多种癌症疾病密切相关。已知PHF6是一个核仁蛋白，参与调控核糖体基因的转录活动。本申请项目试图研究PHF6抑制核糖体基因转录的机制，尤其是探究PHF6沉默核糖体编码区转录的功能机制，研究编码区DNA甲基化抑制PHF6结合的方式，探索PHF6识别组蛋白修饰的种类，分析它参与反义RNA转录的作用方式，验证PHF6通过反义RNA介导的H4K20me3修饰从而抑制编码区转录的功能作用关系，为深入了解PHF6对基因转录的控制机制及其在相关疾病发生的作用提供新的研究信息。

组蛋白修饰阅读器蛋白能够结合特定修饰的染色质进而招募其他表观遗传修饰酶以及转录因子等来达到特异性地抑制或激活基因转录的目的。作为一个阅读器蛋白，本课题试图研究核仁蛋白PPHF6抑制核糖体基因转录的表观遗传机制。研究发现PHF6能够在核糖体的基因体（gene body）上，招募H4K20me3甲基化酶，从而导致rDNA上发生H4K20me3的修饰，从而抑制了核糖体基因的转录。当Dnmt1结合在rDNA基因体上水平下降，则DNA甲基化水平下降，从而造成PHF6结合上升，招募H4K20me3的表观修饰酶，导致基因体H4K20me3的修饰水平上升，以及核糖体基因的转录抑制。本研究为表观遗传调控基因转录提够了新的信息。 ....