Myelin is composed of plasma membrane spirally wrapped around axons and compacted into dense sheaths by myelin-associated proteins. Myelin is elaborated by neuroepithelial derived oligodendrocytes in the central nervous system (CNS) and by neural crest derived Schwann cells in the peripheral nervous system (PNS). While some myelin proteins accumulate in only one lineage, myelin basic protein (Mbp) is expressed in both. Overlapping the Mbp gene is Golli, a transcriptional unit that is expressed widely both within and beyond the nervous system. A super-enhancer domain within the Golli/Mbp locus contains multiple enhancers shown previously to drive reporter construct expression specifically in oligodendrocytes or Schwann cells. In order to determine the contribution of each enhancer to the Golli/Mbp expression program, and to reveal if functional interactions occur among them, we derived mouse lines in which they were deleted, either singly or in different combinations, and relative mRNA accumulation was measured at key stages of early development and at maturity. Although super-enhancers have been shown previously to facilitate interaction among their component enhancers, the enhancers investigated here demonstrated largely additive relationships. However, enhancers demonstrating autonomous activity strictly in one lineage, when missing, were found to significantly reduce output in the other, thus revealing cryptic “stealth” activity. Further, in the absence of a key oligodendrocyte enhancer, Golli accumulation was markedly and uniformly attenuated in all cell types investigated. Our observations suggest a model in which enhancer-mediated DNA-looping and potential super-enhancer properties underlie Golli/Mbp regulatory organization.

髓磷脂由螺旋状包裹轴突的质膜组成，并通过髓磷脂相关蛋白压缩成致密的鞘。髓磷脂由中枢神经系统 (CNS) 中的神经上皮来源的少突胶质细胞和周围神经系统 (PNS) 中的神经嵴来源的雪旺细胞精心制作。虽然一些髓磷脂蛋白仅在一种谱系中积累，但髓磷脂碱性蛋白( Mbp ) 在两种谱系中都有表达。与Mbp基因重叠的是Golli ，这是一种在神经系统内外广泛表达的转录单位。 Golli/Mbp基因座内的超级增强子结构域包含多个增强子，先前显示可驱动报告构建体在少突胶质细胞或雪旺细胞中特异性表达。为了确定每个增强子对Golli/Mbp表达程序的贡献，并揭示它们之间是否发生功能相互作用，我们衍生了单独或以不同组合删除它们的小鼠品系，并测量了相对 mRNA 积累处于早期发展和成熟的关键阶段。虽然超级增强子之前已被证明可以促进其组成增强子之间的相互作用，但这里研究的增强子表现出很大程度上是加性关系。然而，在一个谱系中严格展示自主活动的增强子，当缺失时，会显着减少另一个谱系的输出，从而揭示神秘的“隐形”活动。此外，在缺乏关键的少突胶质细胞增强剂的情况下，在所有研究的细胞类型中， Golli 的积累均显着且均匀地减弱。 我们的观察提出了一个模型，其中增强子介导的 DNA 环和潜在的超级增强子特性是Golli/Mbp调控组织的基础。