Abstract
We hypothesized that the highly controlled pattern of gene expression that is essential for liver regeneration is encoded by an epigenetic code set in quiescent hepatocytes. Here we report that epigenetic and transcriptomic profiling of quiescent and regenerating mouse livers define chromatin states that dictate gene expression and transposon repression. We integrate ATACseq and DNA methylation profiling with ChIPseq for the histone marks H3K4me3, H3K27me3 and H3K9me3 and the histone variant H2AZ to identify 6 chromatin states with distinct functional characteristics. We show that genes involved in proliferation reside in active states, but are marked with H3K27me3 and silenced in quiescent livers. We find that during regeneration, H3K27me3 is depleted from their promoters, facilitating their dynamic expression. These findings demonstrate that hepatic chromatin states in quiescent livers predict gene expression and that pro-regenerative genes are maintained in active chromatin states, but are restrained by H3K27me3, permitting a rapid and synchronized response during regeneration.
Highlights
We hypothesized that the highly controlled pattern of gene expression that is essential for liver regeneration is encoded by an epigenetic code set in quiescent hepatocytes
Gene expression is largely dependent on the combinatorial influence of transcriptional regulators and a highly complex epigenetic code comprised of histone posttranslational modifications, histone variants, DNA modifications, long noncoding RNAs, chromatin remodelers, and other factors[1]
transposable elements (TEs) were sequestered in states categorized as heterochromatin, and we found that the repressive marks that occupy TEs differed according to transposon age
Summary
We hypothesized that the highly controlled pattern of gene expression that is essential for liver regeneration is encoded by an epigenetic code set in quiescent hepatocytes. The collaborative ENCODE and Roadmap projects[29,30,31] and individual investigators have generated extensive datasets to define the epigenetic landscape of stem cells, cancer cells, developing embryos, and many normal tissue types These studies uncovered common patterns of co-occurring epigenetic marks in many cell types, showing that active and repressed chromatin share similar marks in a wide variety of tissues. This has been extended by a systems biology approach that integrates multiple epigenetic marks to identify marks that co-exist at multiple sites in the genome. A recent report from the mouse ENCODE project combined 8 hPTMs across 66 tissue-stages during mouse development to define 15 ChromHMM states, of which most are consistent across tissues and stages, with the exception of the enhancer state, which is highly dynamic[35]
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