Even the most careful criminals leave some kind of evidence; a fingerprint or a strand of hair can be enough for a clever investigator to link them to the scene of the crime. Although it’s far from an open and shut case, new research in mice shows that the epigenome of neurons contains chromatin clues about signals that have come and gone.
The savvy sleuths in the Barco lab (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Spain) created mice that express fluorescent proteins in the nuclear membranes of active neurons in order to dust for epigenomic fingerprints left behind after the cells were stimulated. They injected a glutamate agonist in the hippocampus, to mimic the activity of a seizure, and after 1 hour they found that:
- According to RNA-seq, over 20 000 transcripts in the nucleus are differentially expressed
- The upregulation of plasticity-related genes occurs at the expense of metabolism-related genes
- These transcripts are usually longer than activity-induced transcripts found in the cytoplasm, and contain non-coding RNAs such as enhancer RNAs (eRNA)
- Chromatin accessibility, as measured by ATAC-seq, changes at over 30 000 genomic regions, where the accessible regions within gene bodies overlap with increased binding of RNAPolII (according to ChIP-seq data for this marker of transcriptional activity)
- Although most activity-dependent transcripts overlap with ATAC-seq peaks, only 25% of altered promoters (defined by RNAPolII and H3K4me3 ChIP-seq data) and 10% of enhancers (defined by H3K27ac, H3K2me1 and CREB binding protein ChIP-seq data) overlap with genes that are activity-dependent
- The changes induced by the seizure are more extreme, but partially overlap with gene expression and chromatin accessibility induced by the more natural stimulus of exploring a new environment
Since epigenetic mechanisms are a prime suspect for creating and maintaining long-term memories, the talented team interrogated hippocampal neurons 48 hours after they were stimulated and found:
- Most of the gene expression changes return to normal, but some regions of chromatin have persistent changes in accessibility without altered transcription
- Chromatin loops anchored with CTCF aren’t affected by neuronal activation, but some differentially accessible regions interact more frequently with genes, as measured with Hi-C
- Many of these activity-dependent gene loops revert back to baseline after 48 hours, but some of the newly formed contacts remain
So, even after the burst of gene expression has passed, overall chromatin architecture seems to be a reliable witness of neuronal activity that once was.
You can put on your detective hat and check for chromatin clues yourself, with the original article in Nature Neuroscience, October 2019.