Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Bioinformatics Competence Center, University of Lausanne, 1015 Lausanne, Switzerland; Bioinformatics Competence Center, Swiss Federal Institute of Technology Lausanne, 1015 Lausanne, Switzerland.
Cell. 2023 Aug 31;186(18):3826-3844.e26. doi: 10.1016/j.cell.2023.07.008. Epub 2023 Aug 2.
Previous studies have identified topologically associating domains (TADs) as basic units of genome organization. We present evidence of a previously unreported level of genome folding, where distant TAD pairs, megabases apart, interact to form meta-domains. Within meta-domains, gene promoters and structural intergenic elements present in distant TADs are specifically paired. The associated genes encode neuronal determinants, including those engaged in axonal guidance and adhesion. These long-range associations occur in a large fraction of neurons but support transcription in only a subset of neurons. Meta-domains are formed by diverse transcription factors that are able to pair over long and flexible distances. We present evidence that two such factors, GAF and CTCF, play direct roles in this process. The relative simplicity of higher-order meta-domain interactions in Drosophila, compared with those previously described in mammals, allowed the demonstration that genomes can fold into highly specialized cell-type-specific scaffolds that enable megabase-scale regulatory associations.
先前的研究已经确定了拓扑关联域 (TADs) 作为基因组组织的基本单位。我们提出了一个以前未被报道的基因组折叠水平的证据，即远距离 TAD 对，相隔兆碱基远，相互作用形成超域。在超域中，位于遥远 TAD 中的基因启动子和结构基因间元件被特异性配对。相关基因编码神经元决定因素，包括那些参与轴突导向和黏附的基因。这些长距离的关联发生在很大一部分神经元中，但仅在一部分神经元中支持转录。超域由多种转录因子形成，这些转录因子能够在长而灵活的距离上配对。我们提出的证据表明，两种这样的因子，GAF 和 CTCF，在这个过程中发挥直接作用。与先前在哺乳动物中描述的相比，果蝇中更高阶超域相互作用的相对简单性，使得能够证明基因组可以折叠成高度特化的细胞类型特异性支架，从而实现兆碱基规模的调控关联。
