Abstract
A central hallmark of epigenetic inheritance is the parental transmission of changes in patterns of gene expression to progeny without modification of DNA sequence. Although, the trans-generational conveyance of this molecular memory has been traditionally linked to covalent modification of histone and/or DNA, recent studies suggest a role for proteins that persist or remain bound within chromatin to “bookmark” specific loci for enhanced or potentiated responses in daughter cells immediately following cell division. In this report we describe a role for p300 in enabling gene bookmarking by pre-initiation complexes (PICs) containing RNA polymerase II (pol II), Mediator and TBP. Once formed these complexes require p300 to facilitate reacquisition of protein complex assemblies, chromatin modifications and long range chromatin interactions that enable post-mitotic transmission of transcriptional memory of prior environmental stimuli.
Highlights
Mechanisms for the establishment of cellular memory of gene expression are necessary for the maintenance of cell fate decisions that establish lineages of specialized function in metazoan cells
These prerequisites are met by assemblies of sequence specific DNA binding protein and associated histone modifying and remodeling factors that must survive the massive disruption in chromatin structure and biochemistry that occurs during replication and condensation of mitotic chromatin in order to specify or reestablish genetic programs in daughter cells following mitosis
Specific ‘‘chromatin marking’’ mechanisms include histone modifications, deposition of histone variants, and the targeting by sequence-specific DNA binding transcription factors like HSF1, HSF2, RUNX2, GATA1, FOXA1 and TFIID [3,4,5,6,7,8,9]; which are thought to produce experimentally detectable changes in chromatin structure that persist throughout the cell cycle [10]
Summary
Mechanisms for the establishment of cellular memory of gene expression are necessary for the maintenance of cell fate decisions that establish lineages of specialized function in metazoan cells. In this work we describe the observation that p300 forms stable assemblies with CREB, Mediator, TBP, Cohesin, Brd and pol II, that poise chromatin for transcriptional initiation and the re-acquisition of long range chromatin interactions to permit the post-mitotic, trans-generational transmission of transcriptional memory of prior gene activation expression events across multiple cycles of cell division These findings illustrate that p300 facilitates the epigenetic transmission of inheritable gene expression programs and define and expand the central role for p300 in implementing and maintaining cell fate decisions during cellular differentiation
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