International Research Center for Medical Sciences, Kumamoto UniversityAbstract熊本大学国際先端医学研究機構免疫ゲノム構造学研究室Laboratory of Chromatin Organization in Immune Cell Development,― 35 ―Dendritic cells (DCs), essential for inducing innate and acquired immunity, are derived from bone marrow hematopoietic stem cells. We have been studying the differentiation of dendritic cells and found that transcription factors establish the enhancers of DC lineage-specific genes in myeloid progenitors, leading to gene expression at the mature DC stage 1-3). However, there is a time lag between enhancer activation and gene expression during DC differentiation. Additional events such as chromatin structure change might be involved in this step. In this research project, we aim to elucidate changes in higher-order chromatin structures in DC differentiation and mechanisms underlying the establishment of DC-specific gene expression pattern. Furthermore, we attempted to understand the molecular basis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) tumorigenesis from 3D chromatin structure analysis. To this end, we isolated bone marrow hematopoietic stem cells, DC-lineage progenitor populations, and mature DC subpopulations from mice and performed comprehensive chromatin structure analysis (Hi-C) 4). In genomic regions at DC-specific genes, the 3D chromatin structures were reorganized upon DC differentiation. The transcription factor IRF8 promoted chromatin structure changes in DC progenitors, leading to DC-specific gene induction. Strikingly, the chromatin structures of infection-inducible genes were preestablished in unstimulated DCs. To understand the changes in 3D chromatin structures in BPDCN tumorigenesis, we performed Hi-C in human BPDCN cell lines. We found that promoter-enhancer interactions were newly formed at the MYC gene locus. We are currently analyzing how this interaction is involved in MYC expression and BPDCN tumorigenesis.Chromatin…structure…analysis…in…dendritic…cell…differentiation…and…dendritic…cell-related…cancer…developmentクロマチン高次構造動態からみた樹状細胞分化とその腫瘍化の解析黒滝 大翼Daisuke Kurotaki
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