Biomedical Graduate Studies

Description of Research Expertise

Research Interests
Hematopoietic stem cell biology, Wnt signaling, splicing in normal and malignant hematopoiesis, interaction between mitochondrial function and nuclear splicing, neuropharmacology of bipolar disorder, mechanisms of lithium action, glycogen synthase kinase-3 (GSK-3).

Key words: Wnt, embryo, signaling, signal transduction, developmental biology, lithium, chromatin, epigenetic, hematopoiesis, stem cell, GSK-3, mTOR, behavior, affective disorders. splicing, mitochondria, metabolism

Description of Research
This lab studies the regulation of hematopoietic stem cell function and self-renewal in normal and malignant hematopoiesis, with a focus on myelodysplasia and other hematopoietic neoplasms, interactions between metabolism and splicing, Wnt signaling with a focus on GSK-3, and the molecular mechanisms in the pathogenesis and treatment of neuropsychiatric disorders. Areas of current research include:

1) Wnt and GSK-3 regulation of hematopoietic stem cell (HSC) self-renewal: We are studying the roles of GSK-3 and Wnt signaling in HSC homeostasis in vivo and in primary HSC culture. We are exploring novel ex vivo culture techniques to define the signaling pathways required for and the gene expression profile associated with HSC self-renewal. In collaboration with Wei Tong at CHOP, we are also studying how JAK/STAT signaling interacts with GSK-3 and Wnts to regulate HSC renewal. These experiments are being carried out with mouse and human hematopoietic stem cells, using novel ex vivo culture techniques and stem cell transplantation assays in mice. These experiments also involve flow cytometry and cell sorting, RNA interference, and biochemical analysis of transmembrane signaling pathways. Our long-term interest is to adapt these findings to clinical applications including hematopoietic stem cell transplantation in humans and treatment of bone marrow failure disorders.

2) We have found that driver mutations in MDS and AML alter mitochondrial function and mitochondrial dysfunction reciprocally regulates nuclear splicing, notably of the mitophagy regulator PINK1. Active projects in the lab investigate how somatic mutations in splicing factors, which occur in clonal hematopoiesis, MDS, CMML, and AML, alter mitochondrial function. We also are studying how altered mitochondrial function drives changes in nuclear splicing of the mitophagy regulator PINK1 and potentially other genes.

3) Wnt signaling modifies chromatin architecture to control early development: We have found that Wnt signaling through ß-catenin establishes poised chromatin architecture at Wnt target promoters in the early embryo. We have identified Prmt2 as a histone H3 arginine-8 methyltransferase and shown that it is recruited by ß-catenin to Wnt target gene promoters and is required for dorsal-ventral patterning. We are currently examining the requirement for Prmt2 in other Wnt-regulated contexts in development and in somatic stem cell populations. We are also exploring the regulation of zygotic gene expression before the midblastula transition, focusing on the role of preMBT transcription in germ layer specification. These experiments are being carried out in Xenopus laevis embryos and in mouse hematopoietic stem cells, and involve microinjection, microsurgical procedures, molecular analysis of chromatin structure and gene expression, and biochemical analysis of the Wnt signaling pathway.

4) we are studying the pharmacology of lithium action, currently focusing on the biochemical and biophysical mechanisms underlying lithium inhibition of GSK-3.

Rotation Projects
1. Molecular analysis of hematopoietic stem cell signaling in vivo and in ex vivo culture.

2. Chromatin modifications in response to Wnt signaling in HSCs.

3. Investigating how mutations in splicing factors alter metabolism.

4. Develop a splicing reporter to use in high throughput screening.

5. Identify signals from mitochondria that regulate splicing.

6. Mechanisms of GSK-3 regulation of splicing.

7. Targeting splicing factors and mitophagy in MDS, AML, and CMML.

8. Mechanisms of lithium action in model systems.

Lab personnel:
Yange Cui, postdoctoral fellow
Morgan Grace, research specialist
Bella Briones, research specialist
Justin Wang, undergraduate
Dillon Voss, vising graduate student