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

nf - κ b转录因子家族的激活是机体抵御环境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，缺氧诱导因子（Hypoxia Inducible Factors, hif）是一系列转录因子，它们对环境氧的变化做出反应，并协调转录程序，这是细胞对缺氧环境反应的重要组成部分。一些证据表明NF-kappaB和HIF通路具有内在联系。这两种转录因子都在炎症和缺氧相关的过程中发挥重要作用，这两种应激与加速衰老和健康寿命下降密切相关。SINHCAF （Sin3A， HDAC相关因子）是一种相对未知的蛋白，最初命名为FAM60A。几个小组的工作导致了它的新名称，因为它被确定为与Sin3A-HDAC转录调节复合物相关的蛋白质。SINHCAF已被证明控制干细胞生物学，并在分化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。研究小组已发表和未发表的研究表明，SINHCAF同时控制HIF和NF-kappaB的转录活性。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评估，SINHCAF占据并调节大量NF-kappaB和HIF靶基因（图1）。该数据定义了SIHCAF和HIF/NF-kappaB信号传导之间先前未知的调控联系。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these findings, very little is known about SINHCAF and how it is able to perform its biological functions.Published and unpublished work from the supervisory team has demonstrated that SINHCAF controls both HIF and NF-kappaB transcriptional activity.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.