Dr. Huang’s research interest has been the post-transcriptional regulation of gene expression in the mammalian system. While studying the rules and mechanisms that govern the nucleocytoplasmic transport of mRNAs, she discovered that a subset of SR proteins (originally thought to be only splicing factors) function as a new class of mRNA export factors. These findings have changed some basic conceptions about mRNA nuclear export. Later, she extended her research to a little-studied mRNA nuclear export factor, NXF2, and found that NXF2 acts in concert with the fragile X mental retardation protein to modulate the stability of the mRNA of the major mRNA export factor NXF1, a process which may be important for the normal development and function of neurons and male germ cells. In the past several years, Dr. Huang has become interested in the developmentally regulated RNA-binding protein Lin28, which is highly expressed in human embryonic stem (ES) cells and whose expression is reactivated in diverse human malignancies including ovarian and breast cancers. Using genome-wide approaches, Dr. Huang and her team identified Lin28 as a master post-transcriptional regulator of a subset of genes important for the growth and survival of human ES cells. They also found that Lin28 promotes malignancy through multiple mechanisms. For example, Lin28 regulates BMP4 and collaborates with Oct4 (another major stem cell factor) to affect ovarian cancer microenvironment. In addition, Lin28 stimulates expression of multiple tumor-promoting genes including HER2 at the posttranscriptional level, consistent with the notion that Lin28 overexpression in primary breast tumors is a powerful predictor of poor prognosis.
Recently, Dr. Huang’s research interest has extended to the imprinted, developmentally regulated H19 long noncoding RNA (lncRNA) as a result of her serendipitous discovery of its relationship with the let-7 family of microRNAs. Abundantly expressed in fetal tissues and adult skeletal muscle, H19 has been implicated in human genetic disorders and cancer. However, how H19 acts to regulate gene function has remained enigmatic. Dr. Huang and her team noted that vertebrate H19 harbors binding sites for let-7 microRNAs, which play important roles in development, cancer, and metabolism. Using H19 knockdown and overexpression, combined with in vivo crosslinking and genome-wide transcriptome analysis, they have demonstrated that H19 modulates let-7 availability by acting as a molecular sponge. The physiological significance of this interaction is highlighted in culture where H19 depletion causes precocious muscle differentiation, a phenotype recapitulated by let-7 overexpression. Together, these results reveal an unexpected mode of action of H19 and identify this lncRNA as an important regulator of the major let-7 family of microRNAs. Currently, Dr. Huang’s lab is focusing on the identification and characterization of the molecular composition of H19-associated complexes, which will be followed by determination of biological significance of interactions of H19 with identified RNA and protein components. The ultimate goal of the studies is to gain a comprehensive mechanistic understanding of how H19, through dynamic interactions with associated components, functions to regulate gene expression under both normal and pathological conditions, with a particular focus on metabolism and reproduction.
- Peng S, Maihle NJ, and Huang Y. Pluripotency Factors Lin28 and Oct4 Identify a Subpopulation of Stem Cell-like Cells in Ovarian Cancer. Oncogene, 29:2153-2159, 2010.
- Jin J, Jing W, Lei X-X, Feng C, Peng S, Boris-Lawrie K, and Huang Y. Evidence that Lin28 stimulates translation by recruiting RNA helicase A to polysomes. Nucleic Acids Res, 39:3724-3734, 2011.
- Peng S, Chen L-L, Lei X-X, Yang L, Lin H, Carmichael GG, and Huang Y. Genome-wide studies reveal that Lin28 enhances the translation of genes important for growth and survival of human embryonic stem cells. Stem Cells, 29:496-504, 2011.
- Lei X-X, Xu J, Ma W, Qiao C, Newman MA, Hammond SM, and Huang Y. Determinants of mRNA recognition and translation regulation by Lin28. Nucleic Acids Res, 40:3574-3584, 2012.
- Feng C, Neumeister V, Ma W, Xu J, Lu L, Bordeaux J, Maihle NJ, Rimm DL, Huang Y. Lin28 regulates HER2 and promotes malignancy through multiple mechanisms. Cell Cycle, 11:2486-2494, 2012.
- Qiao C, Ma J, Jie Xu, Xie M, and Huang Y. Drosha-mediated destabilization of Lin28 mRNA targets. Cell Cycle11:3590-3598, 2012.
- Kallen AN, Ma J, and Huang Y. Lin28 may antagonize miRNA-mediated repression by displacing miRISC from target mRNAs. Frontiers in Geneticsdoi:10.3389/fgene.2012.00240, 2012.
- Kallen AN, Zhou XB, Xu J, Qiao C, Ma J, Lei Y, Lu L, Liu C, Yi JS, Zhang H, Min W, Bennett AM, Gregory RI, Ding Y, and Huang Y. The imprinted H19 long noncoding RNA antagonizes let-7 miRNAs. Mol Cell, doi: 10.1016/j.molcel.2013.08.027, 2013.