Discovery of long noncoding RNAs with enhancer function (eRNAs).
We discovered a new class of regulatory long non coding RNAs(lncRNAs) that positively influence neighboring gene expression when expressed from distal sites. Such activating lncRNAs display a similar activity to enhancer elements since they mediate transcriptional activation in a promoter-dependent and orientation-independent manner. We are continuously uncovering the molecular mechanisms of eRNA biogenesis and functions, which will have great potential in cancer therapeutics.
Discovery of the transcriptional and RNA processing complex, Integrator.
We isolated and characterized Integrator, a novel 14-subunit multiprotein complex involved in the 3’-end processing of small nuclear RNAs generated by RNA polymerase II (RNAPII). Integrator contains an enzymatic subunit with close homology to the catalytic subunit of cleavage and polyadenylation specificity factor (CPSF). Later, we also discovered Integrator functions in other aspects of RNA regulation and more.
Discovery of the human microRNA biogenesis and effector complexes.
MicroRNA are processed through a two-step mechanism which is initiated by the enzyme Drosha in the nucleus. However, it was not clear whether Drosha was sufficient to mediate the processing of primary microRNAs. We illustrated the complete molecular definition of a two-subunit complex (Drosha and DGCR8) termed Microprocessor responsible for the initial processing of primary microRNA (miRNA) to precursor miRNA. We also isolated Dicer-TRBP complex which is responsible for loading the mature microRNA onto the Ago proteins, the catalytic engine of the RNA interference machinery.
Discovery of the first histone demethylases for H3K27 and H3K4me3.
H3K4me3 is an activation mark usually found at promoter regions. We identified JARID1d, the first histone demethylase capable of removing H3K4me3 modifications. JARID1d could enhance polycomb protein Ring6a/MBLR functions. This discovery has a significant impact for the field of chromatin regulation by providing new understanding of how histone demethylases mediate repression through recruitment of polycomb proteins. We also found UTX in a multiprotein complex with MLL3/4, the first enzyme complex opposing the action of the polycomb repressive complexes.