Differentiation of oligodendrocytes (OL) from progenitor cells (OPC) is the result of a unique program of gene expression, which is further regulated by the formation of topological domains of association with the nuclear lamina. In this study, we show that cultured OPC were characterized by progressively declining levels of endogenous Lamin B1 (LMNB1) during differentiation into OL. We then identify the genes dynamically associated to the nuclear lamina component LMNB1 during this transition, using a well established technique called DamID, which is based on the ability of a bacterially-derived deoxyadenosine methylase (Dam), to modify genomic regions in close proximity. We expressed a fusion protein containing Dam and LMNB1 in OPC (OPCLMNB1-Dam) and either kept them proliferating or differentiated them into OL (OLLMNB1-Dam) and identified genes that were dynamically associated to LMNB1 with differentiation. Importantly, we identified Lss, the gene encoding for lanosterol synthase, a key enzyme in cholesterol synthesis, as associated to the nuclear lamina in OLLMNB1-Dam. This finding could at least in part explain the lipid dysregulation previously reported for mouse models of ADLD characterized by persistent LMNB1 expression in oligodendrocytes.

中文翻译：

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少突胶质细胞祖细胞分化过程中的动态核纤层蛋白 B1 基因关联。


少突胶质细胞 (OL) 与祖细胞 (OPC) 的分化是独特的基因表达程序的结果，该程序进一步受到与核层相关的拓扑结构域的形成的调节。在这项研究中，我们发现培养的 OPC 的特点是在分化为 OL 过程中内源性核纤层蛋白 B1 (LMNB1) 水平逐渐下降。然后，我们使用一种名为 DamID 的成熟技术来识别在此转变过程中与核纤层成分 LMNB1 动态相关的基因，该技术基于细菌衍生的脱氧腺苷甲基化酶 (Dam) 的能力，修改邻近的基因组区域。我们在 OPC (OPCLMNB1-Dam) 中表达了包含 Dam 和 LMNB1 的融合蛋白，并使它们保持增殖或分化为 OL (OLLMNB1-Dam)，并鉴定了与分化时与 LMNB1 动态相关的基因。重要的是，我们鉴定了 Lss，即编码羊毛甾醇合酶的基因，羊毛甾醇合酶是胆固醇合成的关键酶，与 OLLMNB1-Dam 中的核纤层相关。这一发现至少可以部分解释先前报道的以少突胶质细胞中持续表达 LMNB1 为特征的 ADLD 小鼠模型中的脂质失调。