Epigenetic
Mechanisms of Stem Cell Differentiation
Functional Long Noncoding RNAs in Stem Cell Maintenance and
Differentiation
The discovery that a vast 98% of the mammalian transcriptome consists of non-coding RNAs (nc-RNAs), which have little or no protein-coding potential, took back many by surprise. Initially thought to be mere transcriptional noise, the field of nc-RNAs expanded rapidly as studies showed that such nc-RNAs, especially long non-coding RNAs (lncRNAs), play important roles in gene expression. Characterized as transcripts that are greater than 200 nucleotides in length, lncRNAs are now known to function via diverse mechanisms in controlling gene expression - some examples would include chromatin remodeling, interaction with transcription factors, regulating mRNA stability and acting as miRNA sponges (Fatica et al., Front Med 2015). Studies have indicated that lncRNAs are emerging players in cell differentiation (Ng et al., EMBO J 2012) and developmental processes (Fatica et al., Nat Rev Gen 2014), and thus through collaborations with labs around the world, we strive to identify and functionally annotate lncRNAs that drive neural differentiation. As aberrations in this complex and tightly regulated process are associated with various neurological and psychiatric disorders (Goncalves et al., Cell 2016), our main aim is to gain functional understanding of lncRNA drivers utilizing both bioinformatics analyses and wet-lab experiments to enable refined selection and development of bio-markers and drug targets.
Identifying Neuronal Differentiation Driving Transcription Factors
The function and morphology of specific cell type can be determined by not only DNA sequences but also by epigenetic factors. In contrast with primary DNA sequences, epigenetic factors such as DNA methylation and histone modification can be reversible according to the environment of cells. Until now, many researchers observed epiegenetic changes during cell differentiation. Recently, we suggested that DNA methylation in intragenic CpG islands has a regulatory function in developmental processes based on the correlation between their hypermethylation and gene activation (Lee et al., PNAS 2017). To elucidate more specific differentiation mechanism by epigenetic factors, we generated comprehensive epigenetic data for iPSC, iPSC-derived NPC, iPSC-derived EN and have analyzed epigenetic changes in neural differentiation. In addition, we analyzed physical chromatin interactions of iPSCs and iPSC-derived NPCs. Since it has been known that development related genes are regulated by PRC complex in interconnected structures (Stefan et al., Nat genet 2015), we assumed that the majority of developmental genes were co-regulated by PRC complex and these interactions could be expanded to mechanisms of epigenetic regulation. From results of DNA methylation and chromatin interaction studies, we are investigating the genomic regions that significantly involved in neural development and putative transcription factors that are able to contorl candidate regions.
