1021 – RNA REGULATORS OF CELLULAR FATE

The most common reversible posttranscriptional mRNA modification on mRNA is N6-methyladenosine (m6A). The presence of m6A alters mRNA metabolism including mRNA stability, mRNA splicing, and translation efficiency. The deposition of transcriptome-wide m6A marks depends on the METTL3-METTL14-WTAP-VIRMA-ZC3H13-RBM15 protein complex, in which METTL3 serves as the catalytic subunit. m6A controls cellstate maintenance in a cellular-context dependent manner. Several studies showed that m6A and many of the associated regulators are important for survival and maintenance of the undifferentiated stages of blood stem cells and myeloid leukemia cells. Therapeutics toward METTL3 and other components are currently being developed and in the clinic to target cancer. Thus, it is important to understand how loss of m6A affects both normal and malignant blood development. Stem cells balance cellular fates through asymmetric and symmetric divisions to self-renew or to generate downstream progenitors. Symmetric commitment divisions in stem cells are required for rapid regeneration during tissue damage and stress. The control of symmetric commitment remains poorly define We previously found that mRNA methylation controls symmetric commitment and cell identity of hematopoietic stem cells (HSCs). However, how this important cellular fate step is controlled by m6A remains unclear. We utilize genetic mouse models that lack METTL3 and utilize newly developed tools to measure m6A in blood stem cells. We also utilize loss and gain of function models to understand the key downstream regulators of the m6A program in the blood. Overall, our results indicate that RNA methylation is critical for normal blood homeostasis and may provide a general mechanism for how stem cells regulate differentiation fate choice. We identify novel regulators downstream of m6A and provide a mechanism for the control of symmetric stem cell fate and the inflammatory myeloid differentiation program. The most common reversible posttranscriptional mRNA modification on mRNA is N6-methyladenosine (m6A). The presence of m6A alters mRNA metabolism including mRNA stability, mRNA splicing, and translation efficiency. The deposition of transcriptome-wide m6A marks depends on the METTL3-METTL14-WTAP-VIRMA-ZC3H13-RBM15 protein complex, in which METTL3 serves as the catalytic subunit. m6A controls cellstate maintenance in a cellular-context dependent manner. Several studies showed that m6A and many of the associated regulators are important for survival and maintenance of the undifferentiated stages of blood stem cells and myeloid leukemia cells. Therapeutics toward METTL3 and other components are currently being developed and in the clinic to target cancer. Thus, it is important to understand how loss of m6A affects both normal and malignant blood development. Stem cells balance cellular fates through asymmetric and symmetric divisions to self-renew or to generate downstream progenitors. Symmetric commitment divisions in stem cells are required for rapid regeneration during tissue damage and stress. The control of symmetric commitment remains poorly define We previously found that mRNA methylation controls symmetric commitment and cell identity of hematopoietic stem cells (HSCs). However, how this important cellular fate step is controlled by m6A remains unclear. We utilize genetic mouse models that lack METTL3 and utilize newly developed tools to measure m6A in blood stem cells. We also utilize loss and gain of function models to understand the key downstream regulators of the m6A program in the blood. Overall, our results indicate that RNA methylation is critical for normal blood homeostasis and may provide a general mechanism for how stem cells regulate differentiation fate choice. We identify novel regulators downstream of m6A and provide a mechanism for the control of symmetric stem cell fate and the inflammatory myeloid differentiation program.