Enhancer–promoter specificity in gene transcription: molecular mechanisms and disease associations

Abstract

Although often located at a distance from their target gene promoters, enhancers are the primary genomic determinants of temporal and spatial transcriptional specificity in metazoans. Since the discovery of the first enhancer element in simian virus 40, there has been substantial interest in unraveling the mechanism(s) by which enhancers communicate with their partner promoters to ensure proper gene expression. These research efforts have benefited considerably from the application of increasingly sophisticated sequencing- and imaging-based approaches in conjunction with innovative (epi)genome-editing technologies; however, despite various proposed models, the principles of enhancer–promoter interaction have still not been fully elucidated. In this review, we provide an overview of recent progress in the eukaryotic gene transcription field pertaining to enhancer–promoter specificity. A better understanding of the mechanistic basis of lineage- and context-dependent enhancer–promoter engagement, along with the continued identification of functional enhancers, will provide key insights into the spatiotemporal control of gene expression that can reveal therapeutic opportunities for a range of enhancer-related diseases.

Recruitment of CTCF to the SIRT1 promoter after Oxidative Stress mediates Cardioprotective Transcription

“…CTCF is recruited to low-affinity sites on a cohort of promoters, including SIRT1, in response to CK2-dependent phosphorylation of specific C-terminal serine residues that are adjacent to regions of CTCF suggested to be involved in RNA interactions and mediate RNA-dependent CTCF multimerization 65,66 . These conclusions are in concert with findings of CTCF-dependent interactions with some promoters 78 and genetic data revealing that promoter binding of CTCF can be functionally required for ligand-dependent enhancer:promoter interactions 79–81 . This study reveals that covalent modification of CTCF can serve as a previously unsuspected strategy to regulating signal-dependent DNA binding, thereby serving as a broadly-used component of promoter grammar regulation in metazoans.…”

A suite of enhancer AAVs and transgenic mouse lines for genetic access to cortical cell types

“…Promising vectors were further evaluated for their brain-wide labeling pattern with serial two-photon tomography (STPT), and the cell-type specificity was determined by single-cell RNA sequencing (scRNA-seq) of labeled visual cortex cells (Figure 1B). We also optimized expression from these vectors by enhancer core bashing and concatenation, or expression of recombinase versions that can be combined with reporter mice 20,[26][27][28] . Last, we generated new transgenic driver lines which can be used alone or in combination with enhancer AAVs to genetically access specific cortical populations at the finest taxonomical categories (supertype/cluster-level; Figure 1C).…”