While epigenetic research has often linked single histone modifications to transcriptional outputs, new research in neurons now shows that “it takes two to tango” and a little serotonin, classically known as a neurotransmitter, keeps the transcriptional tango going strong. Specifically, a free-stepping study that discovered histone serotonylation previously associated an adjacent enrichment of the lysine 4 trimethylation and glutamine 5 serotonylation on histone H3 (H3K4me3Q5ser) with active gene expression in serotonergic neurons; however, the underlying mechanisms at play remained undefined.
Now, a part-time dance troupe and full-time research team directed by Haitao Li (Tsinghua University, Beijing, China), Tom W. Muir (Princeton University, NJ, USA), and Ian Maze (Icahn School of Medicine at Mount Sinai, NY, USA) sought to explore the crosstalk between these two histone modifications by evaluating how different patterns of histone modifications affect the binding and activity of relevant histone readers, writers, and erasers.
So, let’s hear how Zhao and colleagues waltzed their way towards some exciting epigenetic findings:
- All tested factors that recognize and bind the H3K4me3 modification (15 purified proteins with PHD finger, Tudor, Chromo, Ssty, and CWZf domains) also bind to the H3K4me3Q5ser dual modification, as evaluated using a carbene-based surface plasmon resonance imaging platform and isothermal titration calorimetry
- Most readers display enhanced or slightly reduced affinity for H3K4me3 in the presence of the “bulky” H3Q5ser modification
- Interestingly, the PHD finger of the Transcription initiation factor TFIID subunit 3 (TAF3) protein favors the dual modification of H3Q5ser alongside any of the methylated forms of H3K4, suggesting that H3Q5ser favors gene transcription
- Additional biochemical studies employing purified recombinant enzymes and peptide/designer chromatin substrates demonstrate that H3Q5ser does not modify the activity of the MLL1 H3K4 methyltransferase
- However, the presence of H3Q5ser inhibits the activity of the KDM5B/C and LSD1 H3K4 demethylase enzymes, most probably by disrupting substrate binding
- A newly developed technique called “chromatin-dipping,” which exposes designer chromatin segments to nuclear extracts, confirmed the results
Overall, this toe-tapping team now provides evidence that H3Q5ser protects H3K4me3 from erasure and supports the binding of basal transcription components to “sustain and augment” specific gene-expression profiles (such as those required in serotonergic neurons) to keep the transcriptional tango going strong. The acrobatic authors hope to next explore the relevance of this mechanism in vivo and evaluate the relevance of other H3Q5 modifications, such as the recently identified dopamine histone modification (H3Q5dop) present in dopaminergic neurons.
For more on how this dual histone modification keeps serotonergic neurons dancing to the beat, see PNAS, February 2021.