Elucidating the Biological Functions of YEATS Domain Containing Proteins in Metabolism Driven Transcriptional Regulation

DNA is the fundamental basis of our genetic information. Throughout evolution, cells have adapted mechanisms that not only allow compaction of DNA into the nucleus, but also maintain easy access to DNA for precise replication, transcription, and damage repair. DNA is wrapped around histone octamers to form nucleosomes, and then a higher-order structure called chromatin. It was revealed that chromatin has regulatory functions for transcription and other biological processes due to its dynamic quality. In eukaryotic organisms, gene regulation is about the balance between compacted DNA and gaining access for RNA polymerase and other regulatory proteins. As the most basic unit of chromatin, a nucleosome has two copies of canonical histones H2A, H2B, H3 and H4 with a segment of about 147 base pairs of DNA. Canonical histones are only expressed in certain times of the cell cycle and they are incorporated into the newly replicated genome. In contrast, histone variants are expressed throughout the cell cycle and are deposited when canonical histones are removed. Histone variants, such as H2A.Z, affect nucleosome properties with distinct modifiable amino acid sequences. Chromatin function is influenced by histone post-translational modifications (PTMs), which can act in a sequential or combinatorial fashion to influence downstream functions. It has been widely acknowledged that histone PTMs such as histone acetylation, crotonylation, and methylation play crucial roles in various biological processes including gene transcription, DNA repair, gene replication, and apoptosis. Additionally, the precursors of histone acetylation and crotonylation, acetyl-CoA and crotonyl-CoA, are regulated by cellular metabolism. This argues that the transcriptional regulatory functions from both PTMs are influenced by cellular metabolism. In recent years, YEATS-domain proteins have gained more appreciation due to their ability to bind both acetylation and crotonylation. As acyllysine readers, YEATS domain proteins amplify the impact of histone acylations on transcriptional regulation through communicating with various transcriptional factors. In budding yeast, there are three YEATS domain proteins: Yaf9, Taf14, and Sas5. Each of them is involved in various essential processes and shows binding preference for specific acylations. Previous work has demonstrated that the YEATS domain of Taf14 binding to crotonylated histone lysine down-regulates pro-growth gene expression during the low oxygen consumption phase, suggesting that transcription is regulated by cellular metabolism through the interactions between YEATS domain and acylation. The work in this dissertation focuses on another YEATS domain protein, Yaf9, and discusses the role it plays in connecting gene expression and cellular metabolism.Doctor of Philosoph