5‐HT2 Receptor Activation Differentially Modulates Linker Histone Kinetics and Histone Deacetylase Activity

Abstract

IntroductionAlterations to chromatin dynamics and histone modification represent crucial processes metazoan cells employ to influence regulation and gene expression. As such, modification to the mobility of the linker histone, the chief component of chromatin compaction and higher‐order chromatin architecture, significantly impacts downstream transcriptional regulation and cellular processing. At present, the contributions of serotonergic signaling to not only heritable epigenetic modification but also higher‐order chromatin structure are a matter of intense research focus. Through both in vitro and in vivo assays, our lab has shown that serotonin 5‐HT2A receptor agonists (psychedelics) exhibit differential efficacy and potency in their ability to prevent inflammatory pathway activation. Modulation to both overall chromatin structure and epigenetic signaling may represent a potential mechanism that psychedelics employ to promote their long‐lasting, therapeutic effects.ObjectivesWe sought to evaluate the impact of chromatin compaction and histone acetylation on 5‐HT2A functional selectivity in human embryonic kidney cells stably expressing the 5‐HT2A receptor.MethodsWe utilized fluorescence recovery after photobleaching (FRAP) to probe the kinetics of the linker histone H1c transiently transfected into the aforementioned HEKH2A cell line. We concurrently measured histone deacetylase (HDAC) activity following exposure to numerous 5‐HT2A agonists.Results5‐HT itself minimally impacts H1c mobility, whereas compounds such as psilocin and the highly selective 5‐HT2 agonist (R)‐2,5‐dimethoxy‐4‐iodoamphetamine [(R)‐DOI] significantly slow H1c kinetics. Interestingly, these changes to linker histone mobility do not correlate with putative epigenetic regulation, as 5‐HT2A compounds with anti‐inflammatory properties reduce histone deacetylase (HDAC) activity, whereas antagonism of the 5‐HT2A receptor induces HDAC activity.ConclusionTogether, this data illustrates that agonism of 5‐HT2A receptors induce unique changes to chromatin architecture and HDAC activity, a conceivable mechanism psychedelics might employ to promote their potent therapeutic properties. Translationally, while HDAC inhibitors have emerged as attractive agents in cancer therapy and asthma treatment, their utility is limited by off‐target toxicity. 5‐HT2A receptor activation represents a potentially more promising therapeutic strategy to modulate histone acetylation patterns for therapeutic effects.Support or Funding InformationSupport from this work was provided in part by the Eleusis Benefit Corporation and the LSU Foundation.