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Topologically-associating domains, TADs, lamina-associated domain, enhancer-promoter specificity, DNA methylation, gene regulation, development, loop extrusion, 3D genome organisation
Abstract:
Cohesin loop extrusion facilitates precise gene expression by continuously driving promoters to
sample all enhancers located within the same topologically-associated domain (TAD). However,
many TADs contain multiple genes with divergent expression patterns, thereby indicating
additional forces further refine how enhancer activities are utilised. Here, we unravel the
mechanisms enabling a new gene, Rex1, to emerge with divergent expression within the ancient
Fat1 TAD in placental mammals. We show that such divergent expression is not determined by a
strict enhancer-promoter compatibility code, intra-TAD position or nuclear envelope-attachment.
Instead, TAD-restructuring in embryonic stem cells (ESCs) separates Rex1 and Fat1 with distinct
proximal enhancers that independently drive their expression. By contrast, in later embryonic
tissues, DNA methylation renders the inactive Rex1 promoter profoundly unresponsive to Fat1
enhancers within the intact TAD. Combined, these features adapted an ancient regulatory
landscape during evolution to support two entirely independent Rex1 and Fat1 expression
programs. Thus, rather than operating only as rigid blocks of co-regulated genes, TAD-regulatory
landscapes can orchestrate complex divergent expression patterns in evolution.
