Researchers from the United States and around the world braved cancelations and layovers to finally find their way to historic Santa Fe New Mexico for the first Keystone Neuroepigenetics meeting. As many locals will brag, Santa Fe is the oldest state capital and also the highest above sea level. The elevation made most attendees a little short of breath, made the drinks seem stronger and, as Peng Jin informed us during his talk, increased the 5hmc levels in our blood. The overall tone of the meeting was focused, close knit, and enthusiastic.
The breadth and depth of the field were showcased throughout the week. A great deal of unpublished work was presented, giving a glimpse of what’s to come over the next year. Everything from the epigenetic roadmap, RNA modifications, histone deacetylases (HDACs) to inhibitors in psychiatric disorders were covered. It’s difficult to pick specific highlights from such a high-calibre meeting, but here are some of the most impactful talks:
Freeing Enhancers with Double Strand Breaks
Li-Huei Tsai, Massachusetts Institute of Technology, USA
One of the event co-organizers, Li-Huei Tasi, presented perhaps the most elegant talk research of the week. Together with colleagues from the Broad institute, Harvard, and MIT, Tasi has been investigating the role of double strand breaks (DSB) in activity-dependent neuronal early-response gene expression.
Using a great deal of experiments and controls, her group has shown conclusively that DSBs are introduced by Topoisomerase IIβ at enhancers of early-response genes. Further, these breaks are necessary and sufficient for early-response gene expression. They propose a model wherein TopoIIβ responds to neuronal activation, and frees enhancers to interact with poised promoters.
ecRNAs Get Active While Neurons Get Turned On
J. David Sweatt, University of Alabama at Birmingham, USA
David Sweatt from the University of Alabama presented some published, and unpublished, work from his lab. He has previously shown that decision making in mice is regulated by DNA methylation. To get at how specific cytosines are targeted for methylation, he has picked up work from Annalisa Di Ruscio on extra-coding RNAs (ecRNAs).
ecRNAs are proposed to be long, unedited transcripts that read through the mRNA transcriptional stop site (i.e. extra-coding material). These long RNAs form secondary structures that bind DNMTs, and target them to their DNA of origin based on their sequence. David Sweatt proposes that this mechanism is also at play in the neurons during stimulation. He presented some very interesting preliminary work suggesting the presence of ecRNAs in the brain during learning.
Pause for Thought: MeCP2 as a Transcriptional Speed Bump in Neuronal Cells
Michael E. Greenberg, Harvard Medical School, USA
Michael Greenburg’s lab at Harvard has spent the last 30 years studying activity-dependent neuronal gene expression. They have shown that HDAC complex removal and eRNA transcription at enhancers is critical for early gene expression. Similarly, they have shown the importance of enhancers in neuronal-specific gene activation. One focus of Michael Greenburg’s talk was the role of the transcriptional regulator MeCP2 in early-gene activation.
MeCP2 accumulates in neurons as synapses form in response to experience at a level comparable to histones, and functions almost like histones at this time. It acts as a repressor of activity-dependent transcription until specific phosphorylations - which the lab is currently mapping – occur. Transcriptomic analysis of genes affected by MeCP2 mutation showed a preference for upregulation of long genes (greater than 100 kb), with overexpression of MeCP2 resulting in down-regulated long genes. Greenburg proposes that MeCP2 may serve as a “speed bump” in long gene bodies to slow the polymerase to increase fidelity. He also speculates that a topoisomerase antagonist may be able to compensate for the MeCP2 mutation.
The Epigenome Roadmap Enhances our Understanding of the Path to Alzheimer’s Disease
Manolis Kellis, Massachusetts Institute of Technology / Broad Institute, USA
Manolis Kellis presented an extremely data-rich talk on his lab’s contribution to the Roadmap Epigenome project. The biggest story out of his talk was the role of immune cells in Alzheimer’s disease (AD). The roadmap shows that enhancers of immune genes are activated in the CK-p25 mouse model of AD, while neuronal enhancers are deactivated, with corresponding changes in gene expression. Most interestingly, these changes occur specifically in the relevant cells types. Kellis proposes that the cell-specific detail of the Roadmap project may shed light on many similarly unsolved complex traits.
Readers of RNA Methylation Reveal Story Behind m6A
Chuan He, University of Chicago, USA
Chuan He from the University of Chicago is part of the group that has lead the development of technologies to examine methyl-, hydroxymethyl-, and other the other cytosine derivatives. He presented an overview of this work with a summary what the group is working on currently. The group is interested in the dynamics of RNA methylation, specifically m6A. He believes the key to understanding RNA methylation function lies in reader proteins. They have identified the YTHF protein family as readers of this mark and show that YTHF1 affects the RNA half-life and promotes translation of bound mRNAs.
The meeting concluded with co-organizer Hongjun Song summing up the meeting. He described the neuroepignome as unique, as it has coopted developmental mechanisms to achieve complex control of activity-dependent gene expression. Most attendees found the meeting a resounding success, and are hopeful for another in two years’ time.
** Thanks to Eric Diehl at The University of Western Ontario, Canada for providing this coverage.