Abstract
Appropriate developmental gene regulation relies on the capacity of gene promoters to integrate inputs from distal regulatory elements, yet how this is achieved remains poorly understood. In embryonic stem cells (ESCs), a subset of silent developmental gene promoters are primed for activation by FBXL19, a CpG island binding protein, through its capacity to recruit CDK-Mediator. How mechanistically these proteins function together to prime genes for activation during differentiation is unknown. Here we discover that in mouse ESCs FBXL19 and CDK-Mediator support long-range interactions between silent gene promoters that rely on FBXL19 for their induction during differentiation and gene regulatory elements. During gene induction, these distal regulatory elements behave in an atypical manner, in that the majority do not acquire histone H3 lysine 27 acetylation and no longer interact with their target gene promoter following gene activation. Despite these atypical features, we demonstrate by targeted deletions that these distal elements are required for appropriate gene induction during differentiation. Together these discoveries demonstrate that CpG-island associated gene promoters can prime genes for activation by communicating with atypical distal gene regulatory elements to achieve appropriate gene expression.
Highlights
Multicellular organism development requires accurate spatio-temporal control of gene expression
FBXL19-responsive genes interact with distal sites that are bound by CDK8 in embryonic stem cells (ESCs)
We found that ∼60% of FBXL19responsive gene promoters interacted with another accessible region of the genome, despite their low transcriptional activity in the ESC state (Figure 1C and Supplementary Figure S1C)
Summary
Multicellular organism development requires accurate spatio-temporal control of gene expression. Gene promoters must integrate gene regulatory inputs in order to create appropriate transcriptional outputs. This is controlled by transcription factors that bind to gene regulatory elements, which are often located at large distances from gene promoters, in some cases several hundred of kilobases away from their target gene [1,2,3,4]. It has been proposed that these elements must communicate to achieve appropriate gene expression In many cases this is thought to rely on direct physical contacts between distal regulatory elements and their target gene promoters [5,6,7]. The molecular mechanisms that underpin these physical interactions remain poorly understood
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