Functional anatomy of distant-acting mammalian enhancers

Abstract

Transcriptional enhancers are a major class of functional element embedded in the vast non-coding portion of the human genome. Acting over large genomic distances, enhancers play critical roles in the tissue and cell type-specific regulation of genes, and there is mounting evidence that they contribute to the aetiology of many human diseases. Methods for genome-wide mapping of enhancer regions are now available, but the functional architecture contained within human enhancer elements remains unclear. Here, we review recent approaches aimed at understanding the functional anatomy of individual enhancer elements, using systematic qualitative and quantitative assessments of mammalian enhancer variants in cultured cells and in vivo . These studies provide direct insight into common architectural characteristics of enhancers including the presence of multiple transcription factor-binding sites and the mixture of both transcriptionally activating and repressing domains within the same enhancer. Despite such progress in understanding the functional composition of enhancers, the inherent complexities of enhancer anatomy continue to limit our ability to predict the impact of sequence changes on in vivo enhancer function. While providing an initial glimpse into the mutability of mammalian enhancers, these observations highlight the continued need for experimental enhancer assessment as genome sequencing becomes routine in the clinic.

Conserved Higher-Order Chromatin Regulates NMDA Receptor Gene Expression and Cognition

“…S3C,D). However, regulatory sites often are comprised of multiple enhancer and transcription factor occupancies sequentially arranged within short genomic distance (Dickel et al, 2013; Factor et al, 2014; Smith and Shilatifard, 2014). Therefore, targeted mutations in proximity to the rs117578877 polymorphism also could affect GRIN2B expression.…”

Spatial genome organization and cognition

“…CEBPB is a transcription factor implicated in consolidation of cortical and hippocampal learning and memory 77–79 . Because many enhancer elements are defined by sequential linear alignment of multiple transcription factors within short distance 80,81 , additional activator proteins may synergistically cooperate with loop-bound CEBPB to regulate GRIN2B expression 23 . Taken together, these findings point to a complex and multilayered regulation of chromosomal conformations within 1Mb surrounding the GRIN2B gene.…”

Human Genetics and Clinical Aspects of Neurodevelopmental Disorders

“…However, it is important to remain humble, as our current state of knowledge is not yet sufficient, albeit steadily increasing, and in principle, any number of nucleotides in the genome, if mutated or modified in a certain way and at a certain time and place, might influence some phenotype during embryogenesis or postnatal life [9,[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] Clinical classifications and the genetic architecture of disease…”