Gene regulatory functions of co-transcriptional histone modifications

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Research in my lab is focused on understanding how genes are turned on and off. Precise gene regulation underlies many important biological functions in humans (and all organisms), including cell growth, cell division, and establishment of proper cell identity during development. Genes are turned on through a highly complex multi-step process. We are interested in some of the early steps in this process, in which protein machines engage with chromosomal DNA and use it as a template to make messenger RNA copies. This process, termed transcription, is highly regulated in cells. For transcription to happen properly, chromosomal DNA needs to be accessible to the proteins that carry it out, and this requires alteration and rearrangement of key DNA packaging proteins called histones. Interestingly, histone modification and rearrangement of histone-DNA structures is an ability that is inherent in within the protein machinery that carries out transcription. An important mechanism that it employs is chemical modification of the histones, which changes their properties to facilitate transcription. The chemical modifications that occur on histones are diverse. Strikingly, patterns of histone modifications that accompany transcription are highly conserved in evolution and are virtually identical at every gene. This suggests that the pattern plays an important role (or roles) in the transcription process, although defining what this is has been challenging. One important consequence of interfering with this pattern, which has been done in experiments with genetically manipulated model organisms, is that transcription tends to happen in inappropriate locations, leading to production of aberrant RNAs. We propose to study the histone modification “landscape” of transcription. Our studies will employ a simple model organism, fission yeast, which can be easily grown and manipulated genetically. Importantly, the histone modification landscape in fission yeast is almost identical to that in human cells. The research program has two broad objectives: 1. Determine how the histone modification landscape regulates gene expression. To do this, we will use detailed biochemical experiments to assess function of modified histones and an array of genetically modified yeast strains. 2. Determine the consequences of “aberrant” transcription for gene regulation. To do this, we will use techniques that allow us to monitor where aberrant transcription occurs throughout the genome. Through these studies, we will arrive at novel, fundamental insights into gene regulatory mechanisms that relate to histone modifications. We will also gain valuable knowledge into how defects in histone modification patterns can disrupt gene regulation.