Abstract
Large fractions of eukaryotic genomes contain repetitive sequences of which the vast majority is derived from transposable elements (TEs). In order to inactivate those potentially harmful elements, host organisms silence TEs via methylation of transposon DNA and packaging into chromatin associated with repressive histone marks. The contribution of individual histone modifications in this process is not completely resolved. Therefore, we aimed to define the role of reversible histone acetylation, a modification commonly associated with transcriptional activity, in transcriptional regulation of murine TEs. We surveyed histone acetylation patterns and expression levels of ten different murine TEs in mouse fibroblasts with altered histone acetylation levels, which was achieved via chemical HDAC inhibition with trichostatin A (TSA), or genetic inactivation of the major deacetylase HDAC1. We found that one LTR retrotransposon family encompassing virus-like 30S elements (VL30) showed significant histone H3 hyperacetylation and strong transcriptional activation in response to TSA treatment. Analysis of VL30 transcripts revealed that increased VL30 transcription is due to enhanced expression of a limited number of genomic elements, with one locus being particularly responsive to HDAC inhibition. Importantly, transcriptional induction of VL30 was entirely dependent on the activation of MAP kinase pathways, resulting in serine 10 phosphorylation at histone H3. Stimulation of MAP kinase cascades together with HDAC inhibition led to simultaneous phosphorylation and acetylation (phosphoacetylation) of histone H3 at the VL30 regulatory region. The presence of the phosphoacetylation mark at VL30 LTRs was linked with full transcriptional activation of the mobile element. Our data indicate that the activity of different TEs is controlled by distinct chromatin modifications. We show that activation of a specific mobile element is linked to a dual epigenetic mark and propose a model whereby phosphoacetylation of histone H3 is crucial for full transcriptional activation of VL30 elements.
Highlights
Our present view on transcriptional regulation has substantially advanced in recent decades
Large fractions are covered by repetitive sequences, many of which are derived from transposable elements (TEs)
By monitoring the expression of ten different types of murine mobile elements, we identified a defined subset of virus-like 30S elements (VL30) transposons reactivated upon increased histone acetylation
Summary
Our present view on transcriptional regulation has substantially advanced in recent decades. The classical model, that the presence of promoter sequences and the availability of transcription factors determine the expression status of corresponding genes, has been extended to a model, in which the accessibility of the DNA is central to transcriptional control. DNA is packed and compacted into chromatin with the nucleosome consisting of DNA and histone proteins as the basic unit. The degree of compaction – either into inaccessible heterochromatin or open euchromatin – has major implications for the transcriptional potential of associated DNA. A way to regulate chromatin accessibility is the posttranslational chemical modification of histone proteins. It can alter chromatin structure and switch genes from a transcriptional repressed to an active state and vice versa [1]
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