Research | The EpiLab

Walters Lab

Dr. Brandon Walters | Psychological & Brain Sciences

Built to Cross Boundaries

Dr. Walters brings an unusually broad scientific foundation to the EpiLab. His training spans genetics, forensic biology, and neuroscience, with a PhD that straddled both electrophysiology and molecular biology. Rather than narrowing after graduation, he made a deliberate choice to diversify further, spending his first postdoc at St. Jude Children's Research Hospital engineering designer stem cells and running high-throughput drug screens. He then joined Dr. Sheena Josselyn's lab at SickKids to round out his training in behavioral neuroscience and viral construct design, before launching the Walters Lab at UTM.

That breadth is intentional. The Walters Lab investigates how m6A RNA methylation is deployed during memory formation and stress, and how its dysregulation contributes to depression. The toolkit reflects the training: molecular, behavioral, and everything in between.

m6A & Memory Formation

N6-methyladenosine (m6A) is the most abundant internal modification on messenger RNA in the brain. These marks are dynamic: written, erased, and read by dedicated proteins in response to cellular activity. This makes m6A well-positioned to serve as a fast, reversible signal during learning.

The Walters Lab investigates how the brain deploys m6A during memory consolidation. Most of our stereotaxic surgeries target the hippocampus, using behavioral tasks including contextual fear conditioning, novel object recognition, and novel object-in-place to probe what animals remember and what they forget.

Stress, Adversity & Depression

Not all of memory is about remembering where you left your keys. The Walters Lab has recently expanded into studying how stress-induced epitranscriptomic changes may contribute to depression-related outcomes.

In collaboration with the McCormick Lab, we use the Social Instability Stress during Adolescence (SIS) model to study how chronic stress during a critical developmental window drives depression-related outcomes in adulthood. We are also developing a maternal separation model in mice in-house, building on prior rat-based work to test whether the paradigm translates across species.

Collaborative Highlight

Engineering a Cre-Inducible sgRNA for Cell-Type-Specific Knockout

One of the more technically demanding constructs produced by the Walters Lab was a Cre-inducible sgRNA built for a collaboration with the Josselyn Lab. The challenge: the U6 promoter that drives sgRNA expression has strict sequence requirements, and there are no introns or stop codons available as conventional "blockers." Solving this required a non-standard molecular engineering approach. This construct enabled cell-type-specific CB1 receptor knockout in PV+ interneurons of the amygdala, contributing to a publication in Cell.

Core Methodology

DART-seq: Reading the m6A Landscape

The Target m6A sits within a canonical consensus sequence, always adjacent to a cytosine (C)

The Reader The YTH domain naturally binds m6A. The Meyer Lab fused mutagen APOBEC1 to it

The Mutation APOBEC1 converts the neighboring C→U, leaving a permanent, sequenceable mark

Expanding DART-seq The Walters Lab modifies DART-seq to expand what it can measure, going beyond m6A localization alone

DART-seq was developed by the Meyer Lab. The Walters Lab builds on this foundation with modified constructs designed to answer questions the original method was not built to ask.

Zovkic Lab

Dr. Iva Zovkic | Psychological & Brain Sciences

An Unlikely Path to a Major Discovery

Dr. Zovkic arrived at epigenetics from an unlikely direction. Trained as a psychologist, she taught herself the molecular toolkit before her postdoc, then made a discovery that would define her lab and the field: that loss of histone variant H2A.Z actually improves memory. It was the first demonstration that histone variants are relevant to memory, establishing chromatin structure as an active regulator of how the brain encodes experience. That finding launched a research program that has since expanded well beyond H2A.Z to encompass the broader landscape of histone variants and the post-translational modifications that regulate them.

The Histone Code, and Beyond

Histones are not passive scaffolds. They carry post-translational modifications, including acetylation, methylation, and phosphorylation, that act as a regulatory code, instructing the cell which genes to activate and which to silence. Histone variants add another layer to this language: by swapping out canonical histones at specific genomic locations, the cell can alter chromatin structure and gene accessibility in ways that go beyond the modification code alone. Together, these two systems give the brain a remarkably precise toolkit for controlling gene expression in response to experience, stress, and disease. Understanding how that toolkit works, and how it breaks down, is the central question of the Zovkic Lab.

Histone Variants in Alzheimer's Disease

Having answered foundational questions about memory, Dr. Zovkic shifted her focus toward disease, drawn to the question of whether the same chromatin mechanisms that regulate healthy memory go wrong in Alzheimer's. The lab investigates how histone variant dysregulation contributes to Alzheimer's disease through an integrated approach: mouse models provide the experimental control needed to establish causal mechanisms, while human patient brain samples ground those findings in the reality of the disease as it presents clinically. By integrating both, the lab can ask not only how chromatin changes drive neurodegeneration in a controlled system, but whether those same changes are present and potentially actionable in the human brain. The goal is a research program where mechanism and clinical relevance inform each other at every step.

Molecular Regulation of the Chromatin Landscape

But the Zovkic Lab's interest doesn't stop at H2A.Z. A broader mechanistic question drives the work: how do histone variants regulate the brain, and what goes wrong in disease? Post-translational modifications to histone variants reshape chromatin architecture and control which genes get expressed, but the rules governing this process in neural contexts are not well understood. A current focus is PARylation of macroH2A and its downstream effects on transcriptional regulation, with the goal of defining how this modification shifts gene expression in neurons and whether its dysregulation contributes to disease.

Core Methodology

ChIP-seq: Mapping the Histone Variant Landscape

The Target

Histone variants occupy specific genomic positions, shaping chromatin accessibility

The Antibody

Variant-specific antibodies pull down DNA wrapped around the histone of interest

The Sequencing

Pulled-down DNA is sequenced genome-wide, mapping variant occupancy across the genome

The Zovkic Approach

Applied across brain regions, conditions, and disease states to track occupancy shifts in AD

ChIP-seq enables the Zovkic Lab to connect molecular chromatin changes to genome-wide transcriptional outcomes in the brain.

Our Research