Research Vision

The brain comprises several specialized cell types, some of which, like neurons and oligodendrocytes, can live for decades or as long as the organism itself. This longevity brings the challenge of maintaining their genomic and epigenomic integrity to preserve cellular function. Our lab investigates the organization of the genome and epigenome in brain cells, focusing on the molecular changes that drive brain aging and neurodegeneration.

Our goal is to understand how alterations in the genetic material and its regulation at the molecular level contribute to functional changes in brain aging and age-related neurological diseases at cellular and organismal scales. To achieve this, we investigate the genome from the linear sequence level to the large-scale 3D architecture of the genome, including enhancer-promoter interactions that regulate gene expression. Within this framework, our immediate focus is on how DNA damage accumulation in aging and neurological diseases disrupts genome organization and integrity. By establishing cause-effect relationships in these processes, we aim to uncover new therapeutic targets to mitigate or reverse brain aging and age-related neurological diseases.

Diagram connecting genomic and epigenomic mechanisms to healthy and aging brain function

Current Projects:

Disruption of Genome Integrity Due to DNA Damage in Alzheimer's Disease

DNA damage is an early hallmark of aging and several age-related neurodegenerative diseases. We aim to understand the levels and distributions of various forms of DNA damage in brain cells and its impact on the integrity of the genome. DNA breaks, when repaired improperly can cause deletions and rearrangements of genome segments. Sometimes these errors can fall within the genes and other regulatory elements, causing significant cellular dysfunction.

An important consideration is the presence of mosaic variations, where these changes may differ between individual cells. To capture these events, we will employ a range of genomic techniques with single-cell resolution.

Diagram of DNA double-strand break hotspots and resulting structural variations

Role of 3D genome organization in neuronal and glial cell function.

The 3D organization of the genome refers to how the genome is spatially arranged within the nucleus of a cell, influencing how genes are accessed and regulated. This structural organization is a critical regulator of genome function, as it affects gene expression, DNA repair, and other cellular processes. Our work, along with others, has uncovered significant remodeling of 3D genome architecture in neurons during learning, memory formation, and neurodegenerative conditions. We investigate how the 3D genome organization in brain cells is regulated as organisms age and how these changes contribute to age-related neurological diseases.

Diagram showing changes in three-dimensional genome organization during neuronal differentiation and memory formation

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Impact of DNA-damaging chemotherapeutic drugs and radiation on the genome of long-lived brain cells.

Chemotherapy-induced cognitive impairment, often referred to as "chemobrain" or "chemofog," is a common side effect of cancer treatments, resulting in persistent cognitive challenges such as memory loss and difficulty with attention, even long after treatment ends. The primary obstacle to preventing or treating chemobrain is our limited understanding of how chemotherapy affects brain cells at a molecular level. Many chemotherapy drugs and radiation therapies work by damaging DNA to eliminate cancer cells. Our research focuses on understanding how this chemotherapy-induced DNA damage disrupts both the genome and the epigenome of brain cells, contributing to cognitive impairment.

Diagram linking chemotherapy and radiation to genomic and epigenomic changes associated with chemobrain