Regulation of gene expression in the brain by the Alzheimer’s disease-implicated transcription factor REST

Abstract

Alzheimer’s disease (AD) is a global challenge. In 2019, AD ranked as the seventh leading cause of death. The development of therapeutic strategies is an urgent requirement to cure or at least to cease the progression of the disease. The transcription factor REST, also known as NRSF play a key role in neuroprotection in the ageing population. The presence of REST in the brains of patients with AD has been shown to be associated with improved cognitive functions. To examine the implication of REST in AD further, the role of REST in the brain was studied using a genetically modified conditional knockout (cKO) mouse model lacking REST in the postnatal forebrain previously generated by the supervisor of this project. Western blot analysis and RNA sequencing approaches were used to determine the mechanisms regulated by REST. The levels of protein products of immediate early genes c-FOS, ARC, EGR1, and NPAS4; memory gene CREB and its active form phospho-CREB; and histone deacetylase HDAC2 were estimated using western blot technique. The western blot analysis revealed a remarkable elevation in levels of c-FOS and a significant decline in ARC levels in the hippocampus and neocortex of Rest cKO genotype when compared with control, along with no significant change in levels of NPAS4 and HDAC2. CREB and phosphorylated CREB levels were reduced in the neocortex; in contrast, CREB levels were elevated along with no change in levels of phosphorylated CREB in the hippocampus of Rest cKO genotype. Furthermore, global transcriptome changes in the hippocampus of Rest cKO compared to control genotype were assessed using RNA-seq, which revealed significant upregulation in Cd74, Apoe, and repression in Oxr1 gene expression in the hippocampus of Rest cKO genotype. Additionally, enrichment analysis using different approaches such as gene ontology enrichment analysis, protein-protein interaction network analysis, and gene set enrichment analysis showed activation of immune response together with impaired myelination and perturbed synaptic processes in Rest cKO genotype in comparison to control. This study signifies the potential role of REST in cellular and molecular processes in the brain. Certainly, Rest cKO genotype exhibited certain molecular changes as seen in AD such as significant elevation in c-FOS levels. A better understanding of the role of REST in the brain can facilitate the discovery of possible novel therapeutic targets relevant to AD.