德国马克斯普朗克分子遗传学研究所Michael I. Robson、Stefan Mundlos等研究人员合作发现，抑制和三维重组可解决演化重排基因组中的调控冲突。相关论文于2022年9月29日发表在《细胞》杂志上。

研究人员报道了一个胎盘哺乳动物的特异性基因Zfp42是如何在一个古老的脊椎动物拓扑相关域（TAD）中出现的，而没有采用或破坏其基因Fat1的保守表达。在ESC中，物理TAD分区将Zfp42和Fat1与驱动其独立表达的不同局部增强子分开。这种分离是由染色质活动而不是CTCF/cohesin驱动的。相反，在胚胎肢体中，无活性的Zfp42分享Fat1完整的TAD，而不对活跃的Fat1增强子作出反应。

然而，无论是Fat1增强子的不相容性还是核包膜的附着力都不能说明Zfp42的无反应性。相反，Zfp42的启动子通过背景依赖的DNA甲基化而对增强子失去作用。因此，不同的机制使独立的Zfp42调控在Fat1基因座上得以整合。重要的是，这种调控的复杂性在演化中似乎很常见，因为在基因组范围内，大多数TAD包含多个独立表达的基因。

据悉，调控景观驱动着复杂的发育基因表达，但仍不清楚在进化过程中纳入新的基因和功能时如何保持其完整性。

附：英文原文

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

Author: Alessa R. Ringel, Quentin Szabo, Andrea M. Chiariello, Konrad Chudzik, Robert Schpflin, Patricia Rothe, Alexandra L. Mattei, Tobias Zehnder, Dermot Harnett, Verena Laupert, Simona Bianco, Sara Hetzel, Juliane Glaser, Mai H.Q. Phan, Magdalena Schindler, Daniel M. Ibrahim, Christina Paliou, Andrea Esposito, Cesar A. Prada-Medina, Stefan A. Haas, Peter Giere, Martin Vingron, Lars Wittler, Alexander Meissner, Mario Nicodemi, Giacomo Cavalli, Frédéric Bantignies, Stefan Mundlos, Michael I. Robson

Issue&Volume: 2022/09/29

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.

DOI: 10.1016/j.cell.2022.09.006

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01128-X