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An eRNA Transcription Checkpoint For Diverse Signal-dependent Enhancer Activation Programs

ABSTRACT: While many or most signal and ligand-dependent pathways function by directing binding of specific transcription factors to large cohorts of regulatory enhancers, the possible “universal” strategies underling activation of these lorge enhancer programs by diverse signals remains poorly understood. Here, we report that ligands, exemplified by estrogen-17-b (E2), cause the recruitment of DNA-PKcs-phosphorylated KAP1 to estrogen receptor a (ERa)-bound enhancers, inhibiting its E3 SUMO ligase activity for the CDK9 subunit of P-TEFb, which permits formation of active P-TEFb required for eRNA elongation overcoming this checkpoint and permitting enhancer activation. We find that most, or all, signal and ligand enhancer activation programs similarly require the loss of SUMOligase function by phoshorylation of KAP1 to prevent Pol II pausing at regulated enhancers. This is based on activation of P-TEFb consequent to deSUMOylation of CDK9, permitting eRNA synthesis. Overcoming this checkpoint appears to be a widely, if not universally, used strategy for signal-dependent enhancer activation because similar events occur on AR and NF-kB-regulated enhancers and even following depolarization acutely-activated neuronal enhancers. This study reveals an unexpected strategy required to overcome a checkpoint common to most or all signal/ligand-regulated enhancers critical to activate broad programs of biologically-important regulatory enhancers that implement the instructions of the endocrine system.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE240599 | GEO | 2024/09/17

REPOSITORIES: GEO

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An eRNA Transcription Checkpoint For Diverse Signal-dependent Enhancer Activation Programs

Project description:While many or most signal and ligand-dependent pathways function by directing binding of specific transcription factors to large cohorts of regulatory enhancers, the possible “universal” strategies underling activation of these lorge enhancer programs by diverse signals remains poorly understood. Here, we report that ligands, exemplified by estrogen-17-b (E2), cause the recruitment of DNA-PKcs-phosphorylated KAP1 to estrogen receptor a (ERa)-bound enhancers, inhibiting its E3 SUMO ligase activity for the CDK9 subunit of P-TEFb, which permits formation of active P-TEFb required for eRNA elongation overcoming this checkpoint and permitting enhancer activation. We find that most, or all, signal and ligand enhancer activation programs similarly require the loss of SUMOligase function by phoshorylation of KAP1 to prevent Pol II pausing at regulated enhancers. This is based on activation of P-TEFb consequent to deSUMOylation of CDK9, permitting eRNA synthesis. Overcoming this checkpoint appears to be a widely, if not universally, used strategy for signal-dependent enhancer activation because similar events occur on AR and NF-kB-regulated enhancers and even following depolarization acutely-activated neuronal enhancers. This study reveals an unexpected strategy required to overcome a checkpoint common to most or all signal/ligand-regulated enhancers critical to activate broad programs of biologically-important regulatory enhancers that implement the instructions of the endocrine system.

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An eRNA Transcription Checkpoint For Diverse Signal-dependent Enhancer Activation Programs [Cut & Tag]

Project description:The evidence that several signal and ligand-dependent pathways function by activating regulatory enhancer programs suggests that a “checkpoint” strategy may underline activation of some or even many diversely-regulated enhancers. Here, we report a molecular mechanism common to several acute signal- and ligand-dependent enhancer activation programs based on release of a shared eRNA transcription checkpoint. This requires recruitment of a DNA-PKcs-phosphorylated RING finger repressor, KAP1, functioning as a modulator, inhibiting its association with 7SK and E3 SUMO ligase activity on the CDK9 subunit of P-TEFb, facilitating formation of an activated P-TEFb complex, licensing eRNA elongation. Overcoming this checkpoint for signal-dependent enhancer activation occurs in diverse pathways including estrogen receptor α, NF-κB-regulated proinflammatory, androgen receptor and neuronal depolarization. Therefore, a specific strategy required to convert a basal state enhancer P-TEFb complex to an active state to release a conserved checkpoint is apparently employed by several functionally-important signal/ligand-regulated regulatory enhancers to implement the instructions of endocrine/paracrine system.

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