I have extensively studied genetics, epigenetics and molecular biology in multiple model systems prior to and during my graduate training in Dr. Edward Chan’s laboratory at the University of Florida. In Dr. Chan’s laboratory, I investigated the molecular mechanisms of microRNA-mediated post-transcriptional gene silencing by the repressor protein GW182 (Yao et al., 2011, Nucleic Acids Res.). I then discovered a novel function for GW182 in controlling miRNA secretion via extracellular vesicles. In addition to these silencing characteristics, I also found that GW182 protected miRNA from degradation by exoribonucleases (Yao et al., 2012, EMBO Rep.). After graduation, I joined Dr. Peng Jin’s lab at Emory University, where I became fascinated by newly-defined cytosine modification derivatives, particularly 5-hydroxymethylcytosine (5hmC), and their potential to play fundamental epigenetic roles in neurodevelopment and brain disorders (Yao et al., 2016, Nat Rev Neurosci.; Yao et al., 2014, Genes Dev.; Yao et al., 2013, Cell Mol Life Sci.). I first followed 5hmC patterns during differentiation of adult mouse hippocampal neural stem cells (NSC). I found that global 5hmC significantly increases during adult NSC differentiation, and that the enzymatic 5hmC “writer” Tet2 is primarily responsible for this effect. Tet2 depletion in NSCs disrupts NSC proliferation and differentiation, and impaires neurogenesis in vivo and in vitro. Genome-wide epigenome and transcriptome analyses reveal important roles for Tet2 in shaping the epigenetic landscape related to neurogenesis. Mechanistically, I showed that Tet2 coordinates with the neural transcription factor Foxo3a to control target gene expression. (Li, Yao et al., Nat Commun., 2017, co-first author).  Given the critical roles of 5hmC in neurogenesis, I was also interested in how 5hmC dysregulation might affect neuronal survival and neurodegeneration. 5hmC is highly enriched in cerebellar motor neuron Purkinje cells (PCs), whose degeneration is the primary cause of many neurodegenerative diseases such as fragile X-associated tremor/ataxia syndrome (FXTAS). Using genome-wide 5hmC profiling of FXTAS mouse model cerebella, I have found remarkable 5hmC alterations before disease onset. These ectopic changes in 5hmC occur in intragenic and distal regulatory regions related to neuronal function and FXTAS pathology (Yao et al., 2013, Hum Mol Genet.). My finding is the first to demonstrate that epigenetic dysregulation of transcription occurs before FXTAS symptom onset and may contribute to FXTAS pathology.  

I also pursued my long-standing interest between RNA binding proteins (RBPs) and gene regulation at both transcriptional and post-transcriptional levels. I discovered a surprising epigenetic role for the classic RBP Lin28A in mouse embryonic stem cells. I found that Lin28A directly binds a consensus DNA sequence in vitro and in vivo to modulate the epigenome and transcriptome. Mechanistically, Lin28A recognizes active transcription “bubbles” and recruits Tet1 to alter 5hmC levels on target loci (Zeng, Yao et al., 2016, Mol. Cell. co-first author, cover story). Sequestration of additional RBPs such as hnRNP A2/B1 by RNA CGG repeats has been suggested as a cause of FXTAS etiology. My unpublished work provides mechanistic evidence that sequestration of hnRNP A2/B1 promotes PC degeneration by cross-talking with epigenetic modifiers. (Yao et al., In preparation).  For decades, cytosine modifications were the only known epigenetic modifications of eukaryotic DNA. A novel adenosine modification, N6-methyladenine (6mA), prevalent in prokaryotes, was recently found in eukaryotic genomes. It is unknown whether 6mA is present in the metazoan brain and how 6mA might exert epigenetic influence on neurodevelopment and function. Through genome-wide 6mA and transcriptome profiling in Drosophila brains and neuronal cells, I found that 6mA serves as an epigenetic mark on key genes involved in neurodevelopment and neuronal activities. (Yao, Li et al., Mol. Cell, first and co-corresponding author). I have found an additional link between environmental stress and 6mA dynamics in mouse brains. Genes bearing these stress-induced 6mA changes significantly associated with neuropsychiatric disorders (Yao, Cheng et al., Nat. Commun., first author).  All of this work provides a strong foundation for establishing my lab in the rapidly expanding field of neuroepigenetics. My lab will focus on two main areas within the field of neuroepigenetics: (1) Roles of DNA modifications, as well as their “readers,” “writers” and “erasers,” in brain function and diseases; and (2) Regulatory RNAs in neurological and neurodegenerative disorders.

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