Uncovering functional interactions between RNA methylation and the epigenome in hematopoietic and malignant stem cells

The development of our blood system is controlled by various mechanisms that regulate gene expression, which in turn affects how blood cells grow, divide, and become specialized. Errors during this process can lead to numerous diseases, including Acute Myeloid Leukemia (AML). Older AML patients often have a low survival rate and endure intensive treatments, emphasizing the need for more effective therapies. Understanding the underlying mechanisms may lead to the discovery of new treatments. Recent research has highlighted that adding a chemical group, known as a methyl group, to RNA plays a significant role in both normal blood development and AML. Historically, research on RNA methylation has primarily focused on its effects on gene expression. However, new findings suggest that this modification also influences how RNA interacts with DNA, affecting the structure and accessibility of our genetic material. This interaction can alter how genes are accessed and utilized, potentially playing a significant role in disease progression. We propose that RNA modifications on transcripts associated with DNA, known as chromatin-associated RNA (caRNA), are vital in shaping DNA accessibility during both normal blood cell development and AML progression. To investigate this, we aim to use advanced techniques to map the methylation of these caRNA and compare it to chromatin accessibility and gene expression in healthy human blood cells. We will examine this in the context of common genetic mutations found in AML by editing human blood cells and comparing these modified cells to AML cells from patients. Additionally, we will create laboratory models using AML cell lines and mice to explore how RNA methylation may influence AML development. This information will help identify key pathways and genes involved in AML progression, potentially leading to the development of novel, innovative treatments for AML and other blood disorders.