Acute Activation of Genes Through Transcriptional Condensates Impact Non-target Genes in a Chromatin Domain

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Abstract Transcription activation of genes by estrogens is driven by enhancers, which are often located within the same Topologically Associating Domain (TAD) as non-targeted promoters. We investigated how acute enhancer-driven activation affects neighbouring non-target genes within the same TAD. Using single-molecule RNA FISH (smFISH), we tracked the transcription of TFF1 (enhancer-targeted) and TFF3 (non-targeted) during estrogen stimulation. We observed mutually exclusive expression patterns: TFF1 expression peaked at 1 hour, while TFF3 reached its peak at 3 hours, after TFF1’s activation had diminished. Chromatin looping data indicated that the enhancer loops with TFF1 but not TFF3, suggesting that TFF3 upregulation is not due to direct enhancer-promoter interactions. CRISPR deletion of the TFF1 enhancer and 1,6-hexanediol (HD) exposure revealed that the TFF1 enhancer:promoter undergo Liquid-Liquid Phase Separation (LLPS), which sequesters the transcriptional machinery and inhibits TFF3 expression. As estrogen signalling wanes or LLPS is disrupted, TFF1 expression declines while TFF3 expression increases. Our findings reveal that enhancer-driven activation can indirectly influence neighbouring genes, highlighting a dynamic shift in gene expression as signalling progresses.

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