Yingqun Huang, MD, PhD

Dr. Huang’s research centers on the mechanistic understanding of metabolic disorders and reproductive tract tumors. Studies from her laboratory have demonstrated that noncoding RNAs play an important role in human health and disease and could serve as potential targets/therapeutics for diabetes and ovarian and endometrial cancers. Her current research interests focus on mechanistic elucidation of TET3-mediated epigenetic regulation of gene expression in the context of metabolic diseases and cancers, with the ultimate goal of discovering new molecular signatures and pathways for preventing and treating these diseases.

Specialized Terms: Gene expresion; Metabolic disorders; Liver; Skeletal muscle; AGRP neurons; cancer

My passion for scientific discovery and “thinking outside the box” have positioned me perfectly for major contributions to the mission of YSM. During graduate and postdoctoral work, I was interested in the rules and mechanisms governing the transport of mRNAs from the nucleus to the cytoplasm. I discovered a subset of SR proteins as a new class of mRNA export factors. These were originally thought to act solely as mRNA splicing factors, but I showed that they also interact with the mRNA export protein NXF1 to promote export. This work changed basic conceptions of mRNA export and my model has become the most widely accepted one for the role of SR proteins in mRNA export.

As an independent investigator, I first studied the function of the stem cell specific RNA binding protein LIN28, which was among four factors shown to reprogram somatic cells to induced pluripotent stem cells. The field once believed that blocking the biogenesis of the microRNA let-7 was the only function of LIN28, but my research showed that LIN28 is also a master posttranscriptional regulator of a subset of mRNAs involved in regulating cell growth and metabolism.

In recent years, my research has extended to the evolutionarily conserved H19 long noncoding RNA. H19 has long been implicated in human genetic disorders and cancer. However, the physiological function and mode of action of H19 have remained elusive. We found that H19 inhibits let-7 function by acting as a molecular “sponge”. This work led to a seminal publication in Molecular Cell in 2013, cited 1038 times. We also found that H19 interacts with and inhibits adenosylhomocysteine hydrolase (SAHH), the only mammalian enzyme capable of hydrolyzing S-adenosylhomocysteine, and a potent feedback inhibitor of SAM-dependent methyltransferases. The work published in Nature Communications in 2015 has been cited 193 times. Given that SAM-dependent methyltransferases direct methylation on a wide range of molecules including DNA, RNA, proteins, and lipids, and that let-7s comprise a major microRNA family known to play important roles in development, cancer and metabolism, our discovery of H19 in regulation of both SAHH and let-7 has the potential of impacting all of these areas. Indeed, we have uncovered novel roles of H19 in glucose metabolism, endometriosis, ovarian and endometrial cancers, and uterine fibroids.

The evolutionarily conserved, liver-enriched transcription factor HNF4a has been extensively studied for its role in hepatic differentiation and function. The gene contains two promoters, P2 and P1, which drive multiple HNF4aisoforms in a development- and tissue-specific manner. It was long thought that the P2-derived isoform predominates during fetal development, however after birth the P1-derived isoform takes over, directing a wide range of liver functions including hepatic glucose production (HGP). In contrast to the long-standing dogma in the field, we discovered epigenetic P2 promoter reactivation in adult liver with an essential role in control of HGP both under physiological and pathological conditions. Using mouse and human primary hepatocytes and mouse models, we demonstrated that this regulation involves H19 and an epigenetic mechanism mediated by TET3 not previously shown to have a role in glucose regulation. Importantly, we showed that inhibition of TET3 or only the P2-specific isoform alleviated type-2 diabetes in both dietary and genetic mouse models. We concluded that the TET3-mediated reactivation of HNF4a P2 promoter and its derived isoform reflect a previously unexpected regulatory mechanism of HGP in adult liver. More recently, we discovered that let-7 mediates metformin-induced inhibition of HGP via targeting the TET3/HNF4a P2 axis and that liver-specific delivery of let-7 ameliorated hyperglycemia and improved glucose homeostasis in mouse models of diabetes.

The TET family of proteins have been well studied in the areas of development, stem cells, and cancer, but their central role in regulation of feeding and energy metabolism had never been documented. We were the first to report that CRISPR-mediated genetic ablation of Tet3 specifically in hypothalamic AGRP induces hyperphagia, obesity and diabetes, in addition to reduction of stress-like behaviors. Mechanistically, TET3 deficiency activates AGRP neurons, simultaneously upregulates the expressions of Agrp, Npy and vesicular GABA transporter Slc32a1, and impedes leptin signaling. In particular, we uncovered a dynamic association of TET3 with the Agrp promoter in response to leptin signaling, which induces association of a chromatin-modifying complex leading to transcription inhibition, and that this regulation occurs both in mouse models and human cells. Our results unmasked TET3 as a critical central regulator of appetite and energy metabolism while revealing its unexpected dual role in control of feeding and other complex behaviors through AGRP neurons.

My current research focuses on mechanistic elucidation of TET3-mediated epigenetic regulation of gene expression in the context of metabolic disorders, inflammatory diseases and cancer, with the ultimate goal of discovering new molecular signatures and pathways for preventing and treating these diseases.