ABSTRACT
Regulatory landscapes drive complex developmental gene expression, but it remains unclear how their integrity is maintained when incorporating novel genes and functions during evolution. Here, we investigated how a placental mammal-specific gene, Zfp42, emerged in an ancient vertebrate topologically associated domain (TAD) without adopting or disrupting the conserved expression of its gene, Fat1. In ESCs, physical TAD partitioning separates Zfp42 and Fat1 with distinct local enhancers that drive their independent expression. This separation is driven by chromatin activity and not CTCF/cohesin. In contrast, in embryonic limbs, inactive Zfp42 shares Fat1's intact TAD without responding to active Fat1 enhancers. However, neither Fat1 enhancer-incompatibility nor nuclear envelope-attachment account for Zfp42's unresponsiveness. Rather, Zfp42's promoter is rendered inert to enhancers by context-dependent DNA methylation. Thus, diverse mechanisms enabled the integration of independent Zfp42 regulation in the Fat1 locus. Critically, such regulatory complexity appears common in evolution as, genome wide, most TADs contain multiple independently expressed genes.
Subject(s)
Chromatin , Placenta , Animals , CCCTC-Binding Factor/metabolism , Chromatin Assembly and Disassembly , Enhancer Elements, Genetic , Evolution, Molecular , Female , Genome , Mammals/metabolism , Placenta/metabolism , Pregnancy , Promoter Regions, Genetic , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
During embryogenesis, precise gene transcription in space and time requires that distal enhancers and promoters communicate by physical proximity within gene regulatory landscapes. To achieve this, regulatory landscapes fold in nuclear space, creating complex 3D structures that influence enhancer-promoter communication and gene expression and that, when disrupted, can cause disease. Here, we provide an overview of how enhancers and promoters construct regulatory landscapes and how multiple scales of 3D chromatin structure sculpt their communication. We focus on emerging views of what enhancer-promoter contacts and chromatin domains physically represent and how two antagonistic fundamental forces-loop extrusion and homotypic attraction-likely form them. We also examine how these same forces spatially separate regulatory landscapes by functional state, thereby creating higher-order compartments that reconfigure during development to enable proper enhancer-promoter communication.
Subject(s)
Chromatin/ultrastructure , Enhancer Elements, Genetic , Gene Expression Regulation, Developmental , Genome , Promoter Regions, Genetic , Transcription, Genetic , Animals , Cell Nucleus/genetics , Cell Nucleus/metabolism , Cell Nucleus/ultrastructure , Chromatin/metabolism , Embryo, Mammalian , Embryonic Development/genetics , Eukaryotic Cells/metabolism , Eukaryotic Cells/ultrastructure , Humans , Molecular ConformationABSTRACT
Comment on: Yien Y, et al. TMEM14C is required for erythroid mitochondrial heme metabolism. J. Clin. Invest. 2014; 124:4294-4304.
