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

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Published and unpublished work from the supervisory team has demonstrated that SINHCAF controls both HIF and NF-kappaB transcriptional activity.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.