Zachary A. Lewis

Chromatin structure and function; Epigenetics; Eukaryotic genome stability; Histone H1

We are interested in understanding epigenetic and chromatin-based mechanisms that contribute to eukaryotic genome function, genome organization, and genome stability. In the nucleus, chromosomal DNA is packaged with histone and non-histone proteins into chromatin. Covalent modification of histone proteins, incorporation of histone variants, and in some organisms, methylation of cytosine bases in DNA all serve to partition chromosomes into distinct structural and functional domains. We are particularly interested in heterochromatin domains, which are highly condensed, transcriptionally silent, and rich in repeated DNA sequences such as transposable elements. Work from several labs has shown that one apparent function of heterochromatin is to preserve genome stability at repeat-rich regions of the genome. We aim to identify components of heterochromatin that perform this function and determine their mechanism of action. For our studies we work with Neurospora crassa, an extremely tractable model fungus that is well suited for investigating chromatin structure and function. Significantly, the molecular composition and genome-level organization of heterochromatin in Neurospora is similar to that of higher eukaryotes, which stands in contrast to a number of other model systems.

A second goal of our lab is to understand the functions and regulation of the linker histone H1. Linker histones are thought to facilitate condensation of the chromatin fiber, but neither the function nor regulation of these proteins is well understood, in part because a microbial model system has not been exploited. The model yeasts do not encode a canonical histone H1 protein. Neurospora, however, contains a single gene encoding a canonical linker histone H1 protein. We are taking advantage of the simple Neurospora system to uncover functions of H1 and determine how this important protein is regulated. For all of our studies, we rely heavily on molecular, genetic, genomic, and proteomic methods.