1. MeCP2: a modulator regulating chromatin higher order structure
MeCP2 is a well-known X-chromosome linked protein. Mutations in the gene encoding MeCP2 are the cause of Rett syndrome (RTT), the most frequent cause of severe mental retardation in females. As indicated by its name, MeCP2 was first discovered through its ability to bind to methylated CpG DNA. It was also reported to bind to nucleosomes, especially the ones with a PTM on H3 (K27me3). More recently, a third chromatin binding target, the hydroxyl-methylated CA repeats on genomic DNA, was revealed. Besides binding to chromatin, MeCP2 recruits many transcription factors such as Nuclear receptor corepressor (NCoR) complex. Disease-associated mutations of MeCP2 largely affect either genome structure or transcription patterns during the neuron cell development, leading to the development of Rett syndrome. Although MeCP2 has been studied for decades, the molecular mechanism of the wild type protein and its mutant forms remain elusive. Our work will focus on how MeCP2 differentiates substrates, and how it recruits other factors to modulate local and globle chromatin architechture.
2. cross-talk between histone modification and m6A modification on RNA transcripts
N6-Methyladenosine (m6A) is the most prevalent internal modification in mRNA, and plays an important role in RNA metabolism and other biological processes. Interestingly, H3K36me3 was shown to guide m6A RNA modification by recruiting a methyltransferase complex (MTC). Reciprocally, the presence of RNA with m6A regulates H3K27me3 and H3K27ac level. Our work will address how H3K36me3 recruits the MTC and how it guides MTC to modify the RNA transcripts during transcription.
3. study the PTMs on chromatin array in vitro
On genome, nucleosomes carry different epigenetic markers even on the same chromatin. It is interesting to design chromatin arrays with various PTMs on different positions. We will idenfiy and characterize the chromatin complexes which simultaneously engage with multiple PTMs on different nucleosomes. This will help us understand more on "histone code" on the chromatin level.