Exploration Of The Molecular Mechanism Of ASH2L, A Core Member Of The Trithoracic Family, In Regulating The Development Of Mouse Cerebral Cortex

Trithorax(TrxG)and Polycomb(PcG)Group Proteins are two evolutionarily conserved histone-modifying complexes with TrxG promoting gene expression by stimulating tri-methylation of lysine-4 in histone H3(H3K4me3)while PcG suppressing gene transcription by stimulating tri-methylation of lysine-27 in histone H3(H3K27me3).The Antagonism and balance between TrxG and PcG have important effects on various life processes such as cell fate determination,organism development and disease process.ASH2L(Absent,Small,Homeotic-2-Like)is a core component of TrxG.Based on the previous work of our lab,we determined that Ash21 conditional knockout(Ash21-cKO)in mouse cerebral cortex inhibits the proliferation ability of neural progenitor cells(NPCs)and Increases NPCs’ apoptosis,the mutant neocortex has fewer neurons,which are also abnormal in composition and laminar position.Through bioinformatics analysis,we found that knockout of Ash21 in the mouse cerebral cortex may inhibit the activivy of Wnt pathway.In our thesis,we further explored the mechanism of ASH2L regulating the development of mouse cerebral cortex.In this study,we verified that the deletion of ASH2L would lead to a decrease in the self-proliferation ability of NPCs by Ash21-shRNA in vivo electroporation.And we further discovered that in Ash21-cKO mouse cortex,the RNA or protein levels of a series of activators of Wnt pathway were down-regulated,and the results of ChIP-seq indicated that ASH2L and H3K4me3 were distributed in the promoter region of the Wnt pathway activator gene(Tcf711,Tcf712,Tcf4,Neurog2,and Celsrl).In vivo Electroporation of pCIG-Δ-β-catenin can rescue the proliferation ability of NPCs.In addition,we also found the disordered expression of cell cycle-related proteins in Ash21-cKO mouse cortex,the inhibited transcription of various potassium channel genes and the decreased protein level of DPY30,a core component of TrxG.In addition,we further discussed the effect of ASH2L in the antagonism and balance between TrxG and PcG.In summary,ASH2L contributes to the H3K4 trimethylation of the promoter region of the Wnt-β-catenindependent signalling related genes,thus activates Wnt signaling to regulate NPCs proliferations.Besides,ASH2L can also regulate the expression of cell cycle related proteins,potassium ion channels and the protein level of TrxG core member DPY30 thus participates in the development of mouse cerebral cortex.