Nanopore sequencing reveals psilocybin-induced brain 5mC/5hmC epigenetic changes | LC 25

Biography

Uri Bertocchi is a PhD candidate in neuroscience at Tel Aviv University's Sagol School of Neuroscience. His research focuses on understanding how psychedelics induce long-lasting epigenetic changes, utilizing cutting-edge technologies like nanopore sequencing. With a multidisciplinary background in neuroscience, psychology, and behavioral epigenetics, Uri is dedicated to advancing mental health research through innovative molecular and computational approaches. He aims to uncover novel insights into psychiatric disorders and their treatment.

Abstract

Psilocybin, a psychedelic compound, has shown significant therapeutic potential, particularly with its long-lasting antidepressant effects. However, the molecular mechanisms that underpin these sustained outcomes are still not fully understood.

This study examines changes in DNA methylation (5mC) and hydroxymethylation (5hmC), which are two key epigenetic modifications believed to play a role in long-term neural plasticity. The dynamic yet stable characteristics of 5mC and 5hmC make them well-suited for regulating persistent changes in gene expression associated with therapeutic effects. 5hmC is prevalent in the brain and is actively involved in DNA demethylation through TET enzymes. Unlike temporary post-translational modifications, 5mC and 5hmC are durable epigenetic markers that have the potential to influence synaptic function and neuronal networks over extended periods.

To investigate these modifications, we employed Oxford Nanopore Technologies PromethION sequencing, a state-of-the-art sequencing platform that can detect 5mC and 5hmC directly without the need for chemical conversion or amplification. The capability of PromethION to generate long reads with high base-resolution sensitivity enables precise mapping of epigenetic modifications in complex brain regions.

Our high-resolution approach revealed significant changes in 5hmC across 1,404 genomic regions that are enriched for pathways essential to synaptic signaling and neural plasticity, while changes in 5mC were minimal.

This research highlights the unmatched advantages of nanopore sequencing in the study of DNA modifications, offering new insights into the epigenetic mechanisms behind psilocybin’s antidepressant effects. By utilizing the unique capabilities of Oxford Nanopore Technologies sequencing, we further our understanding of how psychedelics impact long-term neural function and mental health outcomes.