The Number of Transcription Factor Molecules Loading at an Enhancer Determines Gene Expression Quantity
45 Pages Posted: 20 Nov 2018 Sneak Peek Status: Under ReviewMore...
A single transcription factor (TF) potentially induces both threshold and graded transcription responses via super enhancers (SEs) and typical enhancers (TEs). However, the mechanism by which a TF binds to different types of enhancers to determine gene expression quantity remains to be elucidated. To clarify the mechanism, we performed an integrated analysis of chromatin accessibility, RelA-DNA binding and single-cell transcription for each enhancer in anti-IgM-stimulated mouse primary B lymphocytes. Here we show that SE activity, defined by acetylated histone H3 lysine 27 (H3K27Ac) modifications, was simultaneously quantitatively controlled by chromatin opening and enriched RelA binding, resulting in threshold transcription. Our analysis indicated that the number of RelA binding in open chromatin regions at SEs and TEs was on average five and one, respectively, and that a mathematical model having these differences in TF numbers as parameters could explain enhancer-mediated quantitative transcription differences of individual genes. This study indicates that highly specific on-off expression of TF-enriched SE-targeted genes results in a highly selective epigenetic landscape for cell specificity, in contract to broadly responsive TE-regulated genes that may be responsible for cellular homeostasis.
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