1. Our laboratory studies DNA base modifications and their erasure in the control of gene expression in stem cells and cancer. Our efforts extend to two distinct DNA modification systems: i) erasure of DNA cytosine methylation through Tet-oxidized 5-methylcytosine intermediates; and ii) DNA adenine N6- methylation (6mA), a previously unrecognized form of DNA modification in mammals. We are particularly interested in understanding how writers, sensors and erasers of these marks modulate gene control in embryonic stem cells, and how this process goes awry in cancers such as myeloid leukemia. We use a combination of protein biochemistry, mouse genetics and next-generation sequencing strategies (MeDIP-seq, RNA-seq, RRBS-seq) to address these questions.
We also seek to uncover previously unknown regulators of DNA base modifications in human cells by interrogating bacterial and phage restriction- and counter-restriction associated genes through a bioinformatics pipeline to identify candidate human orthologs.
2. Protein engineering and synthetic signaling pathways
A major focus of our research is the design and construction of controllable, synthetic signaling systems. We apply the design principles of synthetic biology and directed evolution of native protein sensors of modified DNA bases to create controllable signaling modules with user-defined inputs and outputs. These engineered signaling modules are being tested in a range of cell-based therapeutic applications.
Categories: Gene Control, Stem Cells, Cancer, Epigenetics, and DNA Methylation
An Adversarial DNA N6-Methyladenine-Sensor Network Preserves Polycomb SilencingMol Cell. 2019 Jun 20; 74(6):1138-1147. e6. . View in PubMed
An Adversarial DNA N6-Methyladenine-Sensor Network Preserves Polycomb Silencing Mol Cell. 2019 Apr 05. . View in PubMed
Erasure of Tet-Oxidized 5-Methylcytosine by a SRAP Nuclease Cell Rep. 2017 Oct 10; 21(2):482-494. . View in PubMed
The TBC1D15 oncoprotein controls stem cell self-renewal through destabilization of the Numb-p53 complex PLoS One. 2013; 8(2):e57312. . View in PubMed
Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells Proc Natl Acad Sci U S A. 2012 Jan 17; 109(3):829-34. . View in PubMed
Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding Mol Cell. 2003 Nov; 12(5):1213-24. . View in PubMed