Transcriptomic and epigenomic analysis of brain disorders

Our work has brought epigenetic regulation to the forefront of memory research, revealing potential novel therapeutic approaches. We identified the chromatin-modifier HDAC2 as a master regulator of synaptic gene expression and showed that HDAC inhibitors enhance and restore learning and memory, even following severe neurodegeneration. This has ignited research into the therapeutic use of chromatin modifiers.

We are currently interested in understanding the transcriptomic and epigenomic landscape in the major brain cell types in both normal physiological brain function and under pathological disease states. In our previous work using a mouse model of severe neurodegeneration, our lab identified novel enhancers, rather than coding regions, as significant factors with substantial contribution to the genetic risk for Alzheimer’s disease (AD). In particular, we found a marked upregulation of genes and enhancers associated with innate immune responses in both AD mouse models and human AD patients. These results have dramatically altered our understanding of the genetic elements contributing to AD risk, and highlight important roles for epigenetic regulation and immune responses in AD pathogenesis. We subsequently conducted single cell RNA-sequencing of microglia during multiple stages of neurodegeneration in a severe neurodegeneration mouse model. From this study, we established the gene expression signature of microglia in homeostatic state, as well as early-response and late-response microglia. We also found evidence for the heterogeneity of late-response microglia. Currently, we are performing cell type-specific epigenomic analysis, including ATAC-seq and ChIP-seq, and single cell RNA-sequencing in postmortem human brain samples to further understand the roles of different neural cell types – including neurons, astrocytes, oligodendrocytes, and microglia – in AD-related neurodegeneration. In a complimentary approach, we are also teaming up with the laboratory of Ed Boyden at MIT to apply multiplexed RNA in situ hybridization to further delineate the spatial distribution of differentially expressed transcripts in the brain. Other research in the lab centers on studying different neuronal sub-populations during the formation and preservation of long-lasting memories, and determining the epigenetic signature of early life experiences (such as environmental enrichment and resource deprivation) to understand how these events set the brain up for resilience or risk to neuropathology later in life.

In parallel work, we are examining the role of genomic integrity in the development of age-related neurological disorders. We previously found an accumulation of DNA double-stranded breaks (DSBs) in pre-symptomatic animal models of neurodegeneration, and showed that DNA damage is also evident in human neurodegenerative brains. Our work linking genomic instability and neurodegeneration is now overwhelmingly supported by human genetic studies, which identify numerous neurodegenerative disease risk gene products regulating DNA damage repair. In an unexpected twist, we discovered that DSBs are physiologically produced by neuronal activity and necessary for the induction of immediate early gene expression in neurons. In healthy cells, DSBs create a relief of torsional constraint of the regulatory region of genes, which contributes to their rapid induction upon activity stimulation. However, inefficient DSB repair during aging or neurotoxic insults is an early event in the cascade of neurodegeneration. We are currently applying techniques such as Hi-C to investigate how DSB formation impacts the topology of the genome and how DSBs accumulation leads to neuronal demise.

Video: Non-linear dimensionality reduction reveals global gene expression profile relationships across 73’909 individual cells isolated from the human brain. Legend below.