HudsonAlpha scientists identify transcription factors that may be involved in altered gene expression seen in Alzheimer’s disease
The human brain contains many types of cells that work together to ensure it functions properly. As arguably the most important organ in the human body, if something goes amiss with any brain cells or their connections to other cells, varying levels of neurological dysfunction can occur. Many neurological disorders arise from damage to brain cells due to a build-up of misfolded or aggregated proteins in the brain, like the tau protein and the amyloid-beta protein. Specific genes contain the instructions cells need for producing proteins. Changes to those genes can affect the protein production cycle, causing a change in the amount of protein produced or the conformation or quality of that protein.
Alterations to the DNA code itself are only one of the ways that protein production can go awry. A class of proteins called transcription factors are a key component of how genes are expressed, causing a protein product to be made at higher or lower amounts than needed. These transcription factors act without changing the genetic makeup of the gene. These factors bind to DNA and recruit repressors or activators like RNA polymerase that coordinate DNA transcription and, ultimately, translation into a protein.
“Many diseases are caused by mutations in regulatory sequences and in the transcription factors, cofactors, chromatin regulators, and noncoding RNAs that interact with these regions,” says HudsonAlpha faculty investigator Rick Myers, PhD. “My lab is interested in understanding the entire process of how genes are turned off and on and how the levels of the expression of the genes are determined in human cells. We particularly focus on this process in cells of the nervous system and want to identify how this process is affected in the brain during health and disease. The goal is to use this understanding to help mitigate, prevent and possibly even reverse neurological diseases.”
Until recently, technology to study the molecular underpinning of cells interrogated samples containing a mixture of all cells in a tissue. A brain sample, for example, would include neurons, microglia, astrocytes, oligodendrocytes, and other cell types. If there is only one cell subtype involved in the disease pathology, its signal could be masked by more abundant cell types. Techniques to separate individual types of cells were costly, time-consuming, and not always accurate. Looking at individual cells provides scientists with new, more precise information on the genetic and epigenetic differences between the cells of someone with a disease compared to those of someone without the disease.
Scientists at the HudsonAlpha Institute for Biotechnology use cutting-edge single-cell technology to study brain diseases on a cell-by-cell basis. This allows scientists to separate individual types of cells from the rest of the group and look for differences that might contribute to disease onset or progression. HudsonAlpha Faculty Investigator Rick Myers, PhD, and his lab use single-cell genomics to identify genetic contributors to various neurodegenerative diseases like Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and ALS.
In a recent study published in Cell Genomics, the research team, led by senior scientist Lindsay Rizzardi, PhD, used single-cell technologies to measure gene expression and DNA accessibility in post-mortem brain tissue from unaffected donors and those with Alzheimer’s disease. The scientists identified regions of the genome that regulate gene expression in specific cell types, such as neurons and microglia, which are often affected in Alzheimer’s disease.
“By coupling disease-associated changes in gene expression with DNA accessibility data, we were able to link genomic regions with the target genes they regulate,” says Rizzardi. “We identified more than 40,000 disease-specific links. Some of these identified specifically in neurons from Alzheimer’s patients contained binding sites for a transcription factor called ZEB1 that has not been previously associated with Alzheimer’s disease but plays important roles in brain development and cancer.”
The team demonstrated regulatory activity for twelve identified regions, including several linked to the amyloid precursor protein gene, APP, which plays a role in Alzheimer’s disease initiation and progression.
The information the team is uncovering in specific cell types is particularly important for identifying the genes impacted by non-coding DNA variants identified in genetic studies of Alzheimer’s disease. This recently published study provides a broad view of cell type-specific regulatory dysregulation in Alzheimer’s disease and many new avenues of investigation to understand disease progression better.
This study was supported in part by NIH grants 5R01MH110472, 3R01MH110472-03S1, and 5R00AG068271. Additional funding was generously provided by donors to the HudsonAlpha Foundation Memory and Mobility Program and the Leo Fund.