Systematic understanding of RNA-centric mechanisms of gene regulation in chromatin

A major focus of modern RNA research is to understand its regulatory roles beyond its coding potential. In chromatin, diverse types of RNAs are increasingly recognized as regulators of gene expression programs. For example, many short or long noncoding RNAs (ncRNAs) are involved with histone modifications that are important for epigenetic gene regulation. Even nascent RNAs, conventionally viewed as intermediates between genes and proteins, are acknowledged for their regulatory potential as they can affect chromatin-associated proteins (CAPs)’ activities. However, understanding the underlying molecular mechanisms of regulatory RNAs remains challenging. This difficulty arises from RNA's inherent biochemical flexibility, where not only its primary sequence but also its secondary and tertiary structures influence function. Additionally, regulatory RNAs often exhibit evolutionary divergences in a sequence level, complicating the investigation. My laboratory is interested in RNA-mediated gene regulation in chromatin. We use interdisciplinary approaches spanning genetics, computational genomics, and high-throughput biochemical assays to understand the mechanisms of regulatory RNAs in chromatin. Our current projects aim to develop a systematic approach to detecting regulatory RNAs and their functional RNA motifs, based on RNA-protein interactions. Specifically, we will first test whether RNA regulates CAP’s genomic occupancies. Second, we will use RNA-editing-based approach to detect RNAs interacting with a CAP. Third, we will develop a high-throughput assay and computational methods to detect functional RNA elements binding to a CAP, based on RNA-centric deep mutational approach. Lastly, we will check whether functional RNA elements are conserved by considering both sequence and secondary structure. We will apply our approach to a histone modifier, LSD1/KDM1a, and its interaction with RNA, including a long ncRNA, HOTAIR. Our results will provide a deep understanding of LSD1-RNA interactions, as well as present a generalizable approach to study how RNA mediates regulatory roles in chromatin. In addition, as LSD1 is a drug target for many diseases such as cancer and psychiatric disorders, our results will offer insights into the development of RNA-based therapeutic strategies. In parallel to scientific contributions in the field of RNA genomics, we will devote ourselves to motivating and training next-generation scientists to develop interdisciplinary skills and minds to tackle important questions in biology. As biology undergoes a transformative integration with data science and artificial intelligence methodologies, it is vital to use both experimental and computational techniques and interpret them appropriately. Throughout the project, we will provide interdisciplinary training opportunities to trainees.