Research

Charting the function and regulation of the noncoding human genome

A decade after the completion of the Human Genome Project, a new challenge now is to decipher the function and regulation, as well as the complex interplay, of millions of regulatory elements in the human genome.  These elements together govern almost all basic cellular functions, in particular the gene expression control.  Importantly, the mutations of noncoding regulatory elements, such as enhancers and promoters, are associated with various diseases.  My laboratory attempts to contribute to solving this challenge by focusing on the following major directions.  Highly interdisciplinary approaches will be utilized including those of biochemistry and molecular biology, epigenetics/epigenomics, and bioinformatics.

Elucidating the molecular functions of enhancer-derived noncoding RNAs (eRNAs)

Networks of regulatory enhancers dictate distinct cell identities and cellular responses by instructing precise spatiotemporal patterns of gene expression.  However, 36 years after their discovery, enhancer functions and mechanisms remain incompletely understood.  Intriguingly, recent evidence suggests that many, if not all, functional enhancers are themselves transcription units, generating eRNAs.  This observation provides a fundamental insight into the inter-regulation between enhancers and promoters; it also raises crucial questions regarding the regulation of the enhancer transcription and potential roles of non-coding eRNAs (See Figure).

We will use biochemical and omics approaches such as GRO-seq (global run-on sequencing) and CLIP-seq (cross-linking immunoprecipitation and sequencing) to study the targets of selective eRNAs, their protein partners, and potential RNA chemical modifications, which will shed new light on gene regulation, 3D genome organization as well as the development of human disease, such as cancer.

Characterizing the three-dimensional genome architecture in gene regulation and cancer

An amazing feature of eukaryotic nuclei is that as long as 2 meters of DNA in linear length (3 billion base pairs in humans) needs to be packaged into a space of less than 10 um a diameter, while the information stored in all regions of this stretch of DNA can still be very quickly (in minutes or seconds) and effectively retrieved.  To characterize the three-dimensional (3D) genome architecture will offer new insights into the process as to how regulatory elements talk to each other in this highly folded space.  Importantly, it is an increasing realization that many human diseases are associated with the disruption of proper chromatin architecture, raising the possibility that by understanding and modulating the genome architecture, there could be innovative ways to interfere with human disease.  We focus on important chromatin architecture regulators particularly cohesin and condensin complexes, which were found highly mutated in many human cancers, but the underlying mechanisms are unknown.  We will use system-wide genome architecture assays named 4C-seq and HiChIP/PLAC-seq, extensive bioinformatic analyses and mathematic modeling to understand how these molecules intertwine the 3D genome, and how their mutations lead to cancer.

Research Interests:

Genomics, epigenomics, bioinformatics, enhancers, enhancer RNAs (eRNAs), long noncoding RNAs, RNA binding proteins, three-dimensional genome architecture, cohesin and condensin, genomic variations/mutations.