CURRENT RESEARCH INTERESTS
Genomic DNA wrapped around histone proteins to form nucleosomes. N-terminal tails of histones are frequently modified at different residues, combination of which constitutes the histone code – instructions to direct structural organization of chromosomal regions, protein binding and gene activity (Portela and Esteller, 2010). Enhancers are cis-regulatory elements on DNA which can be bound by transcription factors and interact with promoters at long distance to affect gene expression (Visel et al., 2009).
In the lab of Rudolf Jaenisch, Dr. Cheng and colleagues used ChIP-seq techniques to profile histone modifications in embryonic stem cells, neural progenitor cells and differentiated cells and discovered H3K27ac as the mark of active enhancers and proposed a model in which enhancers can exist in poised or active states. Genes proximal to poised enhancers (H3K4me1+ H3K27ac-) are generally not active and encode functions for future states. Active enhancers (H3K27ac+) associate with genes that are active and correspond to functional categories relevant to the current cell state. Acquisition of H3K27ac at enhancers during differentiation is a hallmark for the transition of epigenetic program during cell state transition
Most of the eukaryotes genes are split. Through splicing, introns are removed and exons are joined from pre-mRNA to form mature mRNA transcripts. Pre-mRNA can be alternatively spliced to generate transcript isoforms which in turns encode protein isoforms that can have different properties and functions, expanding the repertoire of the proteome (Nilsen and Graveley, 2010).
Epithelial-mesenchymal transition (EMT) is a developmental program in which epithelial cells adopt mesenchymal fate and acquire motility (Polyak and Weinberg, 2009). It is often exploited by cancer cells to gain motility and properties of stem cells to successfully disseminate and form secondary metastases. In a collaboration of Frank Gertler and Chris Burge Labs, Dr. Cheng and colleagues used RNA-seq to profile splicing changes during EMT in an inducible cellular model. Many of the splicing events observed in the EMT model are conserved among cancer cells and a subset of events as potential markers for classification of patient biopsies were identified. This study also identified ESRP splicing factors as important regulators of splicing during EMT and showed that perturbation of these splicing factors can modify cell adhesion and migratory phenotypes.
In the lab of Chris Burge in a collaboration with Harvey Lodish, Dr. Cheng and colleagues profiled transcriptome of blood cells undergoing erythropoiesis. Through motif analysis, Mbnl1 was identified as a potential regulator of splicing during erythropoiesis. Knockdown of Mbnl1 and some of its predicted targets led to inhibition of erythropoiesis, demonstrating the role of Mbnl1 in regulating transcripts important for erythroid differentiation.