Epitranscriptomic regulation in hematopoietic stem cell niche generation and regeneration

Project summary/Abstract Hematopoietic stem cells (HSCs) rely on the bone marrow niche. Understanding HSC niche generation during development and regeneration after injury will help devise ways to promote HSC function and hematopoiesis. During development, HSCs take residence in the newly established bone marrow niche and remain there for the rest of the adult life. After injury, the bone marrow niche can regenerate to support the recovery of HSCs and hematopoiesis. Mesenchymal stromal cells (MSCs) are key components of the bone marrow HSC niche. However, the mechanisms that regulate the generation and regeneration of the bone marrow MSCs and HSC niche are poorly understood. N6- methyladenosine (m6A) epitranscriptomic mRNA modification has recently emerged as an important regulatory module of gene expression with impacts on many biological processes. We found that deletion of the key m6A methyltransferase Mettl3 leads to HSC niche generation but not maintenance defects. Based on our preliminary data, we propose to investigate the role of m6A on bone marrow HSC niche generation and regeneration. Using the key m6A methyltransferase Mettl3 as an entry point, we will focus on the role of m6A in HSC niche generation during development and regeneration after an injury. We will characterize how m6A regulates the bone marrow HSC niche development in vivo. We will also investigate the role and mechanisms of m6A in bone marrow niche regeneration in vivo. The results of these studies are expected to not only provide new insight into how m6A regulates bone marrow HSC niche generation and regeneration, but also have the potential to identify novel targets to help enhance the bone marrow regeneration and niche function to promote a healthy blood system.