Chromatin Architecture and Gene Regulation in Aging Cells

2012 senior Scholar Award in aging

The literature on aging includes very many papers correlating changes in chromatin structure with aging, including in yeast and mammalian cells. A limitation of these studies is that, until recently, we have had no clear picture of how chromatin architecture is related to gene regulation in specific cases, and in particular how it might affect the ability of transcriptional activators (the primary regulators in eukaryotes) to work. Many past conclusions have relied on general inferences from genome wide studies, invoking such rather poorly defined concepts as “genome compaction”, “nuclease accessibility”, and so on.

Thanks in part to the development of a new quantitative assay for “nucleosome occupancy”, we now have a much clearer picture of what determines nucleosome disposition (positioning) and occupancies, and how these parameters affect gene activation, and, apparently, unwanted basal transcription. The discovery of “partially unwrapped” nucleosomes, and an analysis of their effects, has also suggested unexpected ways that nucleosomes can facilitate as well as hinder access of specific DNA binding proteins to DNA. Also quite unexpectedly, it turns out that the chromatin architecture is strikingly different at a typical yeast promoter compared with that at a mammalian promoter. We are now in a position to ask, for both mammalian and yeast cells, how aging affects these parameters in specific, well-defined cases. We will therefore use established methods for preparing aged and young yeast and mammalian cells, and determine whether and how, for these specific cases, gene regulation goes awry as cells age.