SINHCAF, a previously unknown link between HIF and NF-kappaB signalling

核因子-kappaB转录因子家族的激活形成了抵御环境对生物体威胁的第一道防线之一，并有助于规划适当的细胞反应。同样，低氧诱导因子(HIF)是一个转录因子家族，它响应环境氧的变化并协调转录程序，形成细胞对低氧环境反应的重要组成部分。多条证据表明，核转录因子-kappaB和缺氧诱导因子通路存在内在联系。这两种转录因子都在与炎症和缺氧相关的过程中发挥着重要作用，这两种应激与加速衰老和降低健康寿命密切相关。SINHCAF(Sin3A，HDAC关联因子)是一个相对未知的蛋白质，最初被命名为FAM60A。自从被确定为与Sin3A-HDAC转录调节复合体相关的一种蛋白质以来，几个小组的工作已经导致了它的新名称。SINHCAF已被证明控制干细胞生物学，并在分化的细胞中调节细胞周期、增殖和迁移。尽管有这些发现，但人们对SINHCAF及其如何发挥其生物学功能知之甚少。监督小组已发表和未发表的工作表明，SINHCAF同时控制HIF和NF-kappaB的转录活性。SINHCAF占据并调节大量的NF-kappaB和HIF靶基因，通过全基因组染色质免疫沉淀结合下一代测序(CHIP-SEQ)和RNA-SEQ(图1)进行评估。这些数据定义了SIHCAF和HIF/NF-kappaB信号之间以前未知的调控联系。在这个项目中，学生将研究SINHCAF调控NF-kappaB和HIF的机制。

Activation of the NF-kappaB transcription factor family forms one of the first lines of defence against environmental threats to the organism and helps programme an appropriate cellular response. Similarly, Hypoxia Inducible Factors (HIFs) are a family of transcription factors that respond to changes in environmental oxygen and orchestrate a transcriptional program, which forms an important part of the cellular response to a hypoxic environment. Several lines of evidence have demonstrated that the NF-kappaB and HIF pathways are intrinsically linked. Both transcription factors play an important role in processes associated with inflammation and hypoxia, two stresses closely linked with accelerated ageing and decreased healthspan.SINHCAF (Sin3A, HDAC Associated Factor), is a relatively unknown protein, originally named as FAM60A. Work from several groups has led to its new name since being identified as a protein associated with the Sin3A-HDAC transcriptional regulator complex. SINHCAF has been shown to control stem cell biology, and in differentiated cells it regulates the cell cycle, proliferation and migration. Despite these findings, very little is known about SINHCAF and how it is able to perform its biological functions.Published and unpublished work from the supervisory team has demonstrated that SINHCAF controls both HIF and NF-kappaB transcriptional activity. SINHCAF occupies and regulates a vast number of NF-kappaB and HIF target genes assessed by genome wide Chromatin Immunoprecipitation coupled to next generation Sequencing (ChIP-seq) and RNA-seq (Figure 1). This data defines a previously unknown regulatory link between SIHCAF and HIF/NF-kappaB signalling.In this project the student will investigate the mechanism behind SINHCAF regulation of NF-kappaB and HIF.