Genome Biology of Single Neuron Function and its Modulation with Age

2010 senior Scholar Award in aging

Our bodies are made up of organs, organs are made up of tissues, and tissues are made up of cells. As our body ages, not all parts deteriorate at the same pace. During degeneration of bodily function from age and disease, not all organs are affected equally, not all tissues in an organ are affected in the same way, and in fact, not all cells within a tissue are affected in the same manner. For example, it is well known that age-related degeneration in Alzheimer's disease involves a subset of neurons within a subset of brain regions. Different organs carry out different functions and different tissues also have specialized roles - thus, that they are affected in different ways by age and disease may seem natural. But, at a superficial glance, cells within a tissue seem to all carry out similar function and occupy a similar niche, so why is there a difference in their response to age and disease?

Recently, using single-cell genomic technologies, the labs of PI J. Kim and co-PI Jim Eberwine have discovered that heterogeneity of function extends down to single cells. Using a group of neurons isolated from rat hippocampus that seem identical by standard measures, we showed that individual gene expression and the molecular products of such expression might differ substantially between each cell. Surprisingly, the genome-wide gene expression data seem to suggest that cell types differ not so much by which genes are expressed at what concentration, but by a broad pattern of co-variation. In addition, the molecular products of gene expression show much wider variation in form than previously suspected and this form seems to be related to how much of the molecule is available for further processing (i.e., functional action).

From the above data, we hypothesize that heterogeneity in aging and age-related dysfunction may be due to heterogeneity in genomic function of individual cells. Thus, understanding the role of genomic elements that show cell-to-cell variability may lead to understanding why certain cells show disease traits and while others stay normal. Furthermore, we propose that cellular heterogeneity may have obscured our understanding of the roles of different molecules in age-related dysfunction. Uncovering variability at the single cell level will lead to new models of how molecules function in a cell and to the discovery of novel targets of therapeutics. In this project, we will use single-cell RNA sequencing to identify genomic elements that show cellular variability and then assay the contribution of such cell-specific elements to aging and cell degeneration in Alzheimer's disease models.

Junhyong Kim Ph.D.
University of Pennsylvania