Cis-regulatory elements in the primate brain: from functional specialization to neurodegeneration

Abstract

Over the last decade, the noncoding part of the genome has been shown to harbour thousands of cis-regulatory elements, such as enhancers, that activate well-defined gene expression programs. Here, we charted active enhancers in a multiplicity of human brain regions to understand the role of enhancers in brain regionalization as well as cell type specialization. In addition, as accelerated turnover had been observed at noncoding sequences, enhancer evolution was studied to discover human-specific alterations that not only might have contributed to the emergence of the human brain, but also to the human-specific vulnerability to neurodegenerative disease. To analyze the presence and possible functional consequences of common and rare variation within cis-regulatory elements, an in depth genomic comparison was performed between a control panel and Parkinson’s disease patients for an intronic α–synuclein enhancer. Combined, these data underscore the important role of enhancers in the brain in a range of (evolutionary) processes from functional specialization to neurodegeneration.