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Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes

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Item Type:Article
Title:Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes
Creators Name:Ringel, A.R. and Szabo, Q. and Chiariello, A.M. and Chudzik, K. and Schöpflin, R. and Rothe, P. and Mattei, A.L. and Zehnder, To. and Harnett, D. and Laupert, V. and Bianco, S. and Hetzel, S. and Glaser, J. and Phan, M.H.Q. and Schindler, M. and Ibrahim, D.M. and Paliou, C. and Esposito, A. and Prada-Medina, C.A. and Haas, S.A. and Giere, P. and Vingron, M. and Wittler, L. and Meissner, A. and Nicodemi, M. and Cavalli, G. and Bantignies, F. and Mundlos, S. and Robson, M.I.
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.
Keywords:Topologically Associating Domains, Lamina-Associated Domain, Enhancer-Promoter Specificity, DNA Methylation, Developmental Gene Regulation, Evolution, Loop Extrusion, Cohesin, CTCF, 3D Genome Organization, Animals, Mammals
Source:Cell
ISSN:0092-8674
Publisher:Cell Press
Volume:185
Number:20
Page Range:3689-3704
Date:29 September 2022
Official Publication:https://doi.org/10.1016/j.cell.2022.09.006
PubMed:View item in PubMed

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