Cell
Volume 185, Issue 20, 29 September 2022, Pages 3689-3704.e21
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Article
Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes

https://doi.org/10.1016/j.cell.2022.09.006Get rights and content
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Highlights

  • Novel genes can emerge in evolution without adopting or disrupting existing regulation

  • TADs can be grossly restructured by chromatin activity independently of cohesin/CTCF

  • NE attachment need not block gene activation or enhancer communication

  • Context-dependent promoter silencing can refine enhancer usage in multi-gene TADs

Summary

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.

Keywords

topologically associating domains
lamina-associated domain
enhancer-promoter specificity
DNA methylation
developmental gene regulation
evolution
loop extrusion
cohesin
CTCF
3D genome organization

Data and code availability

  • All data reported in this paper will be shared by the lead contact upon request. This paper analyzes existing, publicly available data whose accession numbers are listed in the key resources table. Sequencing data generated in this study are available at the NCBI Gene Expression Omnibus, GEO: GSE185775.

  • This paper does not report original code.

  • Any additional information required to reanalyze the data reported in this work paper is available from the lead contact upon request.

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Present address: Department of Molecular Life Sciences, University of Zürich, Zurich, Switzerland

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Lead contact