Abstract
Transcriptional activation is accompanied by multiple molecular events that remodel the local chromatin environment in promoter regions. These molecular events are often orchestrated in response to the activation of signalling pathways, as exemplified by the response of immediate early genes such as FOS to ERK MAP kinase signalling. Here, we demonstrate that inducible NFI recruitment permits PARP1 binding to the FOS promoter by a mutually reinforcing loop. PARP1 and its poly(ADP-ribosyl)ation activity are required for maintaining FOS activation kinetics. We also show that the histone variant H2A.Z associates with the FOS promoter and acts in a transcription-suppressive manner. However, in response to ERK pathway signalling, H2A.Z is replaced by H2A; PARP1 activity is required to promote this exchange. Thus, our work has revealed an additional facet of PARP1 function in promoting dynamic remodelling of promoter-associated nucleosomes to allow transcriptional activation in response to cellular signalling.
Highlights
Transcriptional activation in response to cellular signalling involves the orchestrated integration of molecular activities that affect both chromatin structure and the engagement and activation of RNA polymerase
Treatment of cells with the ERK pathway activator PMA promoted rapid inducible binding of PARP1 to the FOS promoter region as little binding was observed to a distal region (Fig 1A; supplementary Fig S1A online)
This increased binding was dependent on the PARylation activity of PARP, as the PARP inhibitor 3AB blocked the increase in PARP1 binding seen on PMA treatment (Fig 1C)
Summary
Transcriptional activation in response to cellular signalling involves the orchestrated integration of molecular activities that affect both chromatin structure and the engagement and activation of RNA polymerase. Following phosphorylation of the transcription factor ELK1, one of the key initial molecular events at the FOS promoter is the enhanced acetylation of the upstream promoter-proximal nucleosome. This in turn leads to greater accessibility of the DNA. PARP1 was linked to transcriptional activation in response to LPS signalling by its ability to modify histones with PAR, thereby destabilising their interactions with DNA and enhancing promoter accessibility [8]. A reciprocal role for PARP1 in promoting ERK-dependent ELK1 phosphorylation and activation was demonstrated [11]
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