Ying Li, PhD

The overall goal of my research is to delineate the epigenetic/epitranscriptomic mechanisms in the regulation of normal hematopoiesis and determine whether and how these critical biological networks are perturbed in myeloid malignancies. 

Having a broad training and expertise in chromatin architecture, genome organization and transcriptional control in normal and malignant hematopoiesis. I employ epigenetic, epitranscriptomic, and bioinformatic approaches to investigate how epigenetic/epitranscriptomic mis-regulation in hematopoietic stem/progenitor cells (HSPCs) leads to malignant transformation. TET2 is one of the most commonly mutated genes in adult myeloid malignancies and normal aging individuals with clonal hematopoiesis, and encodes an enzyme mediating demethylation the methylcytosine in not only DNA, but also RNA. Recently, we started to explore TET2-mediated m5C oxidation of the chromatin associated RNAs (caRNAs) and determined their contribution to the TET2-mediated HSPC regulation and tumor suppressive function. 

Our results showed that TET2 deficiency leads to globally opened chromatin and activation of genes in HSPCs, via impaired m5C oxidation of long terminal repeat caRNAs. We further discovered that the m5C modification on these caRNAs is mainly installed by RNA methyltransferase NSUN2 and recognized by methyl-CpG-binding domain family protein MBD6 that recruits the polycomb repressive H2AK119ub deubiquitylase complex (PR-DUB) to mediate local chromatin activation by erasing H2AK119ub. 

We achieved targeted demethylation (by RNase-defective RfxCas13d-TET2CD) and sterically blockage (with antisense oligonucleotide) of the m5C modification of target repeat RNAs that are hyper-methylated due to TET2 deficiency, which partially restored TET2 loss mediated abnormal HSPC function, consistent with what we observed in Tet2 deficient HSPCs upon knockdown of Nsun2 or Mbd6. Our findings revealed a new TET2-caRNA m5C-MBD6 axis in chromatin and transcription regulation. 

This current project is a natural extension of our recent discovery to uncover the roles of NSUN2 in the control of HSPC gene expression and function via its enzymatic activity on caRNAs. Thus, I have expertise and research skills, knowledge, experience and motivation to successfully accomplish the studies proposed in this project.