2月28日，国际顶级学术期刊Cell发表了东南大学生命科学研究院/“发育与疾病相关基因”教育部重点实验室万亚坤课题组关于“A Role for the Nucleoporin Nup170p in Chromatin Structure and Gene Silencing”的研究成果（Cell, Volume 152, Issue 5, 28 February 2013, Pages 969-983）。该工作由加拿大阿尔伯塔大学、美国系统生物学研究所和东南大学联合完成，受到国家自然基金资助，万亚坤为论文并列第一作者。
端粒是真核生物染色体中基因调控的一个特殊的位点，位于端粒附近的基因其转录活性往往受到抑制。但是，细胞如何精确地调控端粒末端基因转录沉默的作用机理尚不清楚。万亚坤等应用系统生物学手段分析，发现核孔复合物Nup170的缺失能导致端粒位置效应的消失，Nup170与组蛋白泛素化、组蛋白乙酰化、染色质重塑分子等众多参与染色质结构的基因存在着遗传互作，并发现其与染色质重塑分子Sth1之间存在着物理相互作用。研究人员还系统地绘制了Nup170在基因组的结合草图，发现了Nup170与亚端粒的结合依赖于端粒沉默信息分子Sir4途径。
本研究采用系统生物学的研究手段，首次揭示核孔复合物通过与染色质重塑分子作用调控亚端粒区域染色质的结构，进而对位于亚端粒区域的基因转录沉默起着重要的调控作用。解决了长期以来人们对核孔复合物调控亚端粒基因沉默作用机制这一科学难题。亚端粒区的基因转录沉默与细胞衰老、人类疾病密切相关。通过系统地研究核孔复合物对端粒附近基因转录沉默的作用机制，将为探索细胞衰老及相关疾病提供科学依据。
A Role for the Nucleoporin Nup170p in Chromatin Structure and Gene Silencing
David W. Van de Vosse,Yakun Wan,Diego L. Lapetina,Wei-Ming Chen,Jung-Hsien Chiang,John D. Aitchison,Richard W. Wozniak
Highlights
Nup170p physically interacts with Sir4p, Rap1p, and the chromatin remodeler RSC
Nup170p binds and represses expression of subtelomeric and ribosomal protein genes
Nup170p and Sir4p bind cooperatively to subtelomeric DNA
Tethering of subtelomeric chromatin to the NE during G1 phase requires Nup170p
Summary
Embedded in the nuclear envelope, nuclear pore complexes (NPCs) not only regulate nuclear transport but also interface with transcriptionally active euchromatin, largely silenced heterochromatin, as well as the boundaries between these regions. It is unclear what functional role NPCs play in establishing or maintaining these distinct chromatin domains. We report that the yeast NPC protein Nup170p interacts with regions of the genome that contain ribosomal protein and subtelomeric genes, where it functions in nucleosome positioning and as a repressor of transcription. We show that the role of Nup170p in subtelomeric gene silencing is linked to its association with the RSC chromatin-remodeling complex and the silencing factor Sir4p, and that the binding of Nup170p and Sir4p to subtelomeric chromatin is cooperative and necessary for the association of telomeres with the nuclear envelope. Our results establish the NPC as an active participant in silencing and the formation of peripheral heterochromatin.
