부산대학교 도서관

In the mammalian cerebral cortex, the hippocampal primordium (Hcp) occupies a discrete position in the dorsal telencephalic neuroepithelium adjacent to the neocortical primordium (Ncp). We examined transcriptomic and chromatin-level features that distinguish the Hcp from the Ncp in the mouse during the early neurogenic period, embryonic day (E)12.5. ATAC-seq revealed that the Hcp was more accessible than the Ncp at this stage. Motif analysis of the differentially accessible loci in these tissues revealed LHX2 as a candidate transcription factor for modulating gene regulatory networks (GRNs). We analyzed LHX2 occupancy profiles and compared these with transcriptomic data from control and Lhx2 mutant Hcp and Ncp at E12.5. Our results revealed that LHX2 directly regulates distinct genes in the Hcp and Ncp within a set of common pathways that control fundamental aspects of development namely pluripotency, axon pathfinding, Wnt, and Hippo signaling. Loss of Lhx2 caused a decrease in accessibility, specifically in hippocampal chromatin, suggesting that this factor may play a unique role in hippocampal development. We identified 14 genes that were preferentially enriched in the Hcp, for which LHX2 regulates both chromatin accessibility and mRNA expression, which have not thus far been examined in hippocampal development. Together, these results provide mechanistic insight into how LHX2 function in the Hcp may contribute to the process by which the hippocampus acquires features distinct from the neocortex. Author summary: The brain performs an array of functions via functionally specialized structures. We examined how the hippocampus, a structure that is critical for learning and memory, the hippocampus, acquires distinct molecular features from an adjacent structure, the neocortex, which processes different functions. As development proceeds, nuclear DNA, which is packaged into DNA-protein complexes called chromatin, is acted upon by regulatory factors that modulate its accessibility to the molecular machinery that produces messenger RNA (mRNA). Measurements of chromatin accessibility and quantification of gene-specific mRNA production, called gene expression profiling, are key tools to uncover early steps in how stem cells give rise to daughter cells with diverse functional capabilities. We found that the early embryonic hippocampal chromatin was significantly more accessible than that of the neocortex. We identified a regulatory protein, LHX2 that maintains this accessibility selectively in the hippocampus, and also controls the expression of distinct sets of genes in the hippocampus and the neocortex. Finally, we identified 14 LHX2 target genes that are important candidates for regulating hippocampal development. Our integrated multiomics approach offers an insight into how the hippocampus and the neocortex develop their unique neuronal compositions which underlie their specialized functions. [ABSTRACT FROM AUTHOR]