The role of Spt5 in enhancer-mediated gene regulation

All biological species are fundamentally derived from the genetic information encoded in their DNA or RNA. The products of gene expression, either proteins or RNA, form the structural and chemical basis for all cellular activities, such as growth of tissues and organs, the immune response to foreign pathogens and development. To accomplish this, gene expression must be tightly regulated to ensure that the right genes are expressed at the right time and at the desired level of expression. Indeed, errors in gene regulation lead to numerous diseases and pathological abnormalities including autoimmune, neurological and developmental disorders, and cancer. Therefore, from both clinical and biological perspectives, it is of great importance to understand how genes are regulated. Specifically, this proposal deals with the role of unique DNA sequences called enhancers. Enhancers modulate the timing and levels of gene expression during organismal development, response to stimuli and immunity, and are therefore a major focus of research in gene regulation. Enhancers can function at large distances from their target genes, and they accomplish this function by making physical contacts with their targets. Given the diversity and complexity of enhancer sequences in the genome, there remain many open questions about how enhancers function at the molecular level. In particular, a major goal in gene regulation research is to identity and characterize the proteins and RNAs that are associated with different classes of enhancers and which regulate its activity. In this regard, the proposed research aims to address how a specific protein, Spt5, regulates gene expression by controlling the activity of enhancers. Using state-of-the-art molecular biology and computational tools, we aim to identify which enhancers are regulated by Spt5, and determine their functional properties. Our goal is to understand how Spt5 regulates enhancer function and what makes some enhancers more sensitive to Spt5 than others. We expect that these studies will be a step forward in our understanding of enhancer biology and gene regulation generally.

All biological species are fundamentally derived from the genetic information encoded in their DNA or RNA. The products of gene expression, either proteins or RNA, form the structural and chemical basis for all cellular activities, such as growth of tissues and organs, the immune response to foreign pathogens and development. To accomplish this, gene expression must be tightly regulated to ensure that the right genes are expressed at the right time and at the desired level of expression. Indeed, errors in gene regulation lead to numerous diseases and pathological abnormalities including autoimmune, neurological and developmental disorders, and cancer. Therefore, from both clinical and biological perspectives, it is of great importance to understand how genes are regulated. Specifically, this project dealt with the role of unique DNA sequences called enhancers. Enhancers modulate the timing and levels of gene expression during organismal development, response to stimuli and immunity, and are therefore a major focus of research in gene regulation. Enhancers can function at large distances from their target genes, and they accomplish this function by making physical contacts with their targets. Given the diversity and complexity of enhancer sequences in the genome, there remain many open questions about how enhancers function at the molecular level. In particular, a major goal in gene regulation research is to identity and characterize the proteins and RNAs that are associated with different classes of enhancers and which regulate its activity. In this regard, the proposed research aimed to address how a specific protein, Spt5, regulated gene expression by controlling the activity of enhancers. Using state-of-the-art molecular biology and computational tools, we studied which enhancers were regulated by Spt5. Surprisingly, we found that very few enhancers were affected by loss of Spt5. This implies that not all enhancers function the same way and that Spt5 is not a general regulator of enhancer function. In addition, we also found important principles that regulate how physical contact is established between enhancers and target genes. In summary, these studies have helped better our understanding of enhancer biology and gene regulation generally and have opened new questions for future research.