Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters

• Published in: Nature communications Vol. 13; no. 1; pp. 4342 - 16
• Main Authors: Robles-Rebollo, Irene, Cuartero, Sergi, Canellas-Socias, Adria, Wells, Sarah, Karimi, Mohammad M., Mereu, Elisabetta, Chivu, Alexandra G., Heyn, Holger, Whilding, Chad, Dormann, Dirk, Marguerat, Samuel, Rioja, Inmaculada, Prinjha, Rab K., Stumpf, Michael P. H., Fisher, Amanda G., Merkenschlager, Matthias
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/32; 38; 38/91; 631/337/572; 631/80/386; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Cohesin; Cohesins; Cohesion; Coupling; Enhancer Elements, Genetic - genetics; Enhancers; Gene expression; Gene sequencing; Genes; Humanities and Social Sciences; Immune response; Innate immunity; Kinases; multidisciplinary; Probability; Promoters; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31192-9

Innate immune responses rely on inducible gene expression programmes which, in contrast to steady-state transcription, are highly dependent on cohesin. Here we address transcriptional parameters underlying this cohesin-dependence by single-molecule RNA-FISH and single-cell RNA-sequencing. We show that inducible innate immune genes are regulated predominantly by an increase in the probability of active transcription, and that probabilities of enhancer and promoter transcription are coordinated. Cohesin has no major impact on the fraction of transcribed inducible enhancers, or the number of mature mRNAs produced per transcribing cell. Cohesin is, however, required for coupling the probabilities of enhancer and promoter transcription. Enhancer-promoter coupling may not be explained by spatial proximity alone, and at the model locus Il12b can be disrupted by selective inhibition of the cohesinopathy-associated BET bromodomain BD2. Our data identify discrete steps in enhancer-mediated inducible gene expression that differ in cohesin-dependence, and suggest that cohesin and BD2 may act on shared pathways. Here the authors show inducible genes and enhancers are regulated mainly by transcriptional burst frequency and that this is coordinated in single cells and individual alleles. Cohesin, which is important for inducible gene expression, is largely dispensable for regulating enhancer burst frequencies; however, it is required for coupling burst frequencies of inducible enhancers and promoters.