Grant: Operating Grant

The human genome (and indeed, the genome of every animal) is comprised of long strands of DNA (known as chromosomes) that need to be tightly packaged within cells. An important consequence of this packaging is that it limits access of cellular gene expression machinery to the genetic information, and thus cells have evolved elaborate mechanisms to regulate DNA packaging. In cells, DNA strands are compacted by wrapping around groups of dedicated packaging proteins called histones. By introducing modifications onto the histones, cells can modulate how DNA is packaged to allow access to certain DNA sequences such as genes. Intriguingly, these modifications can also serve as signals that help to localize cellular machinery involved in gene expression to specific regions of the chromosome. I study one such modification called ubiquitylation. Histone ubiquitylation has been detected in a wide variety of organisms, including humans, and altered levels of this modification are associated with certain types of cancer. However, its function in modulating DNA packaging and gene expression is still poorly understood. Using a model organism that is easy to manipulate genetically (the fission yeast Schizossacharomyces pombe), I have found that cells unable to ubiquitylate their histones suffer from gene expression defects, morphological abnormalities and slow growth. I have also linked ubiquitylation to the function of other known regulators of gene expression using genetic and biochemical approaches. My current experiments involve using high-resolution RNA sequencing technology to identify which genes are affected by ubiquitylation and which stage of gene expression is compromised. I hope to characterize in detail how the ubiquitylation of histones contributes to the proper regulation of genes. Ultimately, such information may provide insight into how gene regulation may be perturbed in disease states such as cancer.