A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory

ABSTRACT

Short-term and long-term transcriptional memory is the phenomenon whereby the kinetics or magnitude of gene induction is enhanced following a prior induction period. Short-term memory persists within one cell generation or in postmitotic cells, while long-term memory can survive multiple rounds of cell division. We have developed a tissue culture model to study the epigenetic basis for long-term transcriptional memory (LTTM) and subsequently used this model to better understand the epigenetic mechanisms that enable heritable memory of temporary stimuli. We find that a pulse of transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) induces LTTM on a subset of target genes that survives nine cell divisions. The chromatin landscape at genes that acquire LTTM is more repressed than at those genes that do not exhibit memory, akin to a latent state. We show through chromatin immunoprecipitation (ChIP) and chemical inhibitor studies that RNA polymerase II (Pol II) elongation is important for establishing memory in this model but that Pol II itself is not retained as part of the memory mechanism. More generally, our work reveals that a transcription factor involved in lineage specification can induce LTTM and that failure to rerepress chromatin is one epigenetic mechanism underlying transcriptional memory.

KEYWORDS:

• trained immunity
• transcriptional memory
• epigenetic
• priming
• inflammation
• chromatin

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Article of Significant Interest Selected from This Issue by the Editors

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00372-16.

ACKNOWLEDGMENTS

We thank Yun Zhu and Wei Wang for undertaking some initial bioinformatic analysis for this project. We also thank Esteban Ballestar for reading the manuscript and providing scientific input. The chemical inhibitors used in this study were kindly provided by Cheryl Arrowsmith of the Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.

A.I.-B. conceived of the project, conducted most of the experiments in the transdifferentiation system, and was the primary author of the manuscript. S.C. performed all bioinformatic analysis included in the paper and aided in writing the manuscript. B.L. performed key ChIP experiments. C.V.O. performed key ChIP experiments, provided ChIP-Seq data, and helped in revising the manuscript. K.-K.C. aided in RT-qPCR analysis. D.T. supervised the bioinformatic analysis. T.G. supervised the progress of this work and substantially aided in writing the manuscript. Y.S. supervised the project from inception.