Genome organization controls transcriptional dynamics during development

• Published in: Science (American Association for the Advancement of Science) Vol. 375; no. 6580; pp. 566 - 570
• Main Authors: Batut, Philippe J., Bing, Xin Yang, Sisco, Zachary, Raimundo, João, Levo, Michal, Levine, Michael S.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 04.02.2022
• Subjects: Animals; Chromatin - chemistry; Chromatin - genetics; Chromosomes, Insect - chemistry; Chromosomes, Insect - genetics; Drosophila - embryology; Drosophila - genetics; Embryos; Enhancer Elements, Genetic; Gene expression; Gene Expression Regulation, Developmental; Genes, Homeobox; Genes, Insect; Genome, Insect; Genomes; HOX gene; Promoter Regions, Genetic; Regulatory Sequences, Nucleic Acid; Single-Cell Analysis; Tethering; Transcription; Transcription, Genetic
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abi7178

Past studies offer contradictory claims for the role of genome organization in the regulation of gene activity. Here, we show through high-resolution chromosome conformation analysis that the Drosophila genome is organized by two independent classes of regulatory sequences, tethering elements and insulators. Quantitative live imaging and targeted genome editing demonstrate that this two-tiered organization is critical for the precise temporal dynamics of Hox gene transcription during development. Tethering elements mediate long-range enhancer-promoter interactions and foster fast activation kinetics. Conversely, the boundaries of topologically associating domains (TADs) prevent spurious interactions with enhancers and silencers located in neighboring TADs. These two levels of genome organization operate independently of one another to ensure precision of transcriptional dynamics and the reliability of complex patterning processes. The role of genome organization in the regulation of gene activity during development has been the subject of considerable controversy. Batut et al . present evidence that dedicated “tethering elements” help to establish long-range enhancer-promoter interactions in the Drosophila genome (see the Perspective by Gaskill and Harrison). Single-cell imaging of transcription in living embryos shows the importance of these elements in determining the timing of Hox gene activation during development. Tethers operate independently of boundary elements, which mediate the opposite function of blocking spurious regulatory interactions between neighboring loci. This work sheds light on how genome organization controls the dynamics of gene expression underlying complex developmental processes. —BAP Tethering elements foster long-range regulatory interactions to promote rapid activation of Hox genes in developing Drosophila embryos.