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 longterm 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/EBP␣) 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.

Evidence for additive and synergistic action of mammalian enhancers during cell fate determination

“…Consistent with this, we find that chromatin opening follows C/EBPα binding and that this results in subsequent enhancer transcription. These observations are consistent with the capacity of the pioneering factor C/EBPα to induce DNA opening ( Iberg-Badeaux et al, 2017 ; van Oevelen et al, 2015 ), and its ability to reorganize chromatin states and genome architecture before gene expression changes ( Stadhouders et al, 2018 ). It remains controversial whether enhancer transcription is required for enhancer priming ( Calo and Wysocka, 2013 ; Dorighi et al, 2017 ; Kaikkonen et al, 2013 ), but our data support that in our system the chromatin modification H3K4me1 generally precedes nucleosome depletion and enhancer transcription ( Bonn et al, 2012 ; Creyghton et al, 2010 ; Rada-Iglesias et al, 2011 ; Wamstad et al, 2012 ).…”

Innate Immune Training of Human Macrophages by Cathelicidin Analogs

“…In our model, pre-incubation with pan-methylation inhibitor MTA did not abolish DCATH-2 training of dTHP-1 cells. Similarly, long-term transcriptional memory in a B cell to macrophage differentiation model was found to be independent of H3K4 methylation ( 60 ). In this model, LPS restimulation was correlated to repressive histone H3K27me3 mark demethylation.…”

Transcriptional Responses of Cancer Cells to Heat Shock-Inducing Stimuli Involve Amplification of Robust HSF1 Binding

“…HSR is often ectopically activated in cancers: arsenic is a transforming agent that in addition to mutations can induce epigenetic changes (54), and heat has been recently shown to induce transcriptional memory (45). Changes prompted by stimuli should depend on transcriptional responses to activate transcription factor binding to DNA, but not necessarily transcription (55).…”