xinyang zhaoAssociate Professor

Research Areas
Hematopoiesis and hematological malignancies

Research Interests

My research interestis focused on understanding the molecular mechanisms involved in normal hematopoiesis as well as hematological malignancies including leukemia and pre-leukemia diseases such as myeloid proliferative neoplasm and myelodysplasia syndrome (MDS). Right now my research is funded by NIH and leukemia research foundation.

1. To understand PRMT1-mediated metabolic reprogramming in leukemogenesis.
We elucidate that protein arginine methyltransferases 1 (PRMT1) methylates an RNA binding protein called RBM15 and thus controls the RBM15 protein stability. RBM15 is required for the metabolic stress response of hematopoietic stem cell for self-renewal, and is involved in chromosome translocation with MKL1 in acute megakaryocytic leukemia (AMKL). In this project, I will address how the PRMT1-RBM15 axis regulates metabolic pathways, which are criticalfor AMKL progression.

2. To understand PRMT1-mediated RNA splicing pathways in MDS.
We have demonstrated that alternative RNA splicing of a few key transcription factors pivotal for hematopoiesis is regulated by the PRMT1-RBM15 axis. Enhanced interaction between RBM15 and SF3B1 K700E mutant found in MDS patients dysregulates alternative RNA splicing of transcription factors. Given that more than 70% of MDS have mutations in splicing factors, understanding the RNA splicing codes recognized by RBM15 will hold a key to design precision medicine for MDS.

3. To understand PRMT1-controled signaling pathways in hematopoiesis and leukemogenesis.
My lab has discovered that PRMT1 methylates a dual specific phosphatase called DUSP4. DUSP4 is a chromatin-associated phosphatase which can directly relay mitogen-activated protein (MAP)kinase signals to cause epigenetic changes. Methylation of DUSP4 by PRMT1 leads to its degradation and blockage of megakaryocyte differentiation. In collaboration with scientists at Memorial Sloan Kettering Cancer Center and Cold Spring Harbor Lab, my lab is using single cell RNA-seq technology and CRSPR-Cas technology to analyze pathways regulated by the PRMT1-DUSP4 axis. We are attempting to purify the E3 ligase which is responsible for recognizing the methylated DUSP4 using biochemical approaches. The role this PRMT1-DUSP4 pathway in leukemogenesis is being studied with PRMT1 transgenic mouse models.

4. To understand the role of long non-coding RNA genes in hematopoiesis.
My lab has reported how RBM15 protein translation is regulated by along noncoding RNA (AS-RBM15). Given that little is known about the biological roles of long noncoding RNAs in hematology, the endeavor in my lab will open up new frontiers to understand hematopoiesis and cancer.

5. To develop therapeutic approaches by inhibiting PRMT activities for cancer and cardiovascular diseases.
We have been developing methods to target PRMT1, 4 and 5 for leukemia treatment for many years. In collaboration with biological chemists at Memorial Sloan Kettering Cancer Center and University of Georgia, we have a few potent and specific PRMT1, PRMT4 and PRMT5 inhibitors. Preliminary studies of using these inhibitors have yielded promising data on treating acute myeloid leukemia and cardiovascular diseases. We are now using patient xenograft models to test these inhibitors.

Xinyang Insert

The PRMT1-DUSP4-p38 kinase axis  in megakaryocyte differentiation.
A collection of signaling and epigenetic events needs to be orchestrated for normal development of hematopoietic lineages. While mitogen-activated protein (MAP) kinases (MAPK) and multiple epigenetic modulators have been implicated in the megakaryocytic (Mk) cell differentiation, the underlying molecular mechanisms of signaling-epigenetic crosstalk remain unclear. MAPKs are in general inactivated by dual specificity phosphatases (DUSPs), whose activities are tightly regulated by various posttranslational modifications. Using knockdown screening and single cell expression analysis, we determined that DUSP4 is the phosphatase that inactivates p38 MAPK in hematopoietic cells and serves as a key regulator to promote megakaryocytic differentiation. Previously, we reported that the activation of PRMT1 delays Mk differentiation. With the next-generation Bioorthogonal Profiling of Protein Methylation technology for live cells, we identified DUSP4 as a PRMT1 substrate. Mechanistically, PRMT1-mediated Arg351 methylation of DUSP4 triggers its ubiquitinylation-mediated degradation by E3 ligase HUWE1, which results in p38 MAPK activation and inhibition of megakaryocytic differentiation in vitro and in vivo. Collectively, these results demonstrate a critical role of PRMT1-mediated posttranslational modification of DUSP4 in regulation of Mk differentiation and maturation. In the context of thrombocytopenia observed in myelodysplastic syndromes (MDS), we demonstrated that high levels of p38 MAPK and PRMT1 are associated with low platelet counts and adverse prognosis, while pharmacological inhibition of p38 MAPK or PRMT1 stimulates megakaryopoiesis in MDS samples. These findings provide novel mechanistic insights into the therapeutic targeting of the DUSP4-p38-PRMT1 axis for treatment of thrombocytopenia associated with myeloid malignancies such as MDS.

Review Here.


Graduate School
Ph.D., SUNY at Buffalo, New York

Postdoctoral Fellowship
Cold Spring Harbor Lab, and Memorial Sloan-Kettering Cancer Center


Shelby Biomedical Research Building
Room 703
1825 University Blvd.
Birmingham, AL 35294-2182

(205) 975-5016