Chromatin, formed from highly regulated interactions of DNA with the histone proteins (H2A, H2B, H3 and H4), helps eukaryotes regulate genome integrity, transcriptional, and epigenetic pathways. Histone proteins can be post-translationally modified (PTM) at select residues, which include lysine methylation and acetylation. These histone PTMs recruit protein complexes that further modulate the activity of the nearby chromatin environment (Jenuwein and Allis et. al., 2001). However, the mechanistic details of how histone PTMs modify enzymatic activities on chromatin remain poorly understood. Previously, our lab discovered a novel histone PTM on histone H3, H3K23me3, which protects highly repetitive regions of the genome during meiosis in T. thermophila and C. elegans (Papazyan et. al., 2014). Recently we showed that a lysine demethylase, KDM4B, selectively associates with H3K23me3 in differentiating mammalian sperm and that the H3K23me3-KDM4B interaction leads to demethylation of H3K36me3, in vitro (Su et. al., 2016). A combination of published work (Fujiwara et. al., 2016) and unpublished data from our lab show that both H3K23me3 and KDM4B are also highly enriched in newly differentiated mammalian neurons in brain tissue and in cultured neurons. Interestingly, this published work also found that mutations in the KDM4 family are associated with neurodevelopmental diseases, but other sites of histone demethylation, by KDM4B, are not known. Based on our previous findings, I hypothesize that the H3K23me3-KDM4B interaction protects chromatin of differentiating neurons against DNA damage during differentiation. This project aims to unravel the molecular mechanisms surrounding the chromatin dynamics of differentiating mammalian neurons. My overall goal of this proposal is to better understand the roles of H3K23me3 and KDM4B during neuronal differentiation.
Multicellular eukaryotes rely on stem cell maintenance to renew tissues of different cell lineages and much of this maintenance is regulated at the chromatin level. This project aims to demystify the molecular underpinnings surrounding the chromatin dynamics of neuronal stem cell differentiation. Our work has the potential to reveal the epigenetic contributions to brain development and elucidate how perturbations in the histone code play a role in neurodevelopmental diseases.
