TRANSCRIPTIONAL REGULATORS OF THE GOLLI/MYELIN BASIC PROTEIN LOCUS INTEGRATE ADDITIVE AND STEALTH ACTIVITIES

Myelin is composed of plasma membrane spirally wrapped around axons and compacted into dense sheaths by myelin associated proteins. In the central nervous system (CNS), myelin is elaborated by neuroepithelial derived oligodendrocytes and in the peripheral nervous system (PNS) by neural crest derived Schwann cells. While some myelin proteins are unique to 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 examine if interactions among these enhancers occur, we derived mouse lines in which enhancers were deleted, either singly or in different combinations, and relative mRNA accumulation was measured at key stages of development. Although super-enhancers have been shown to facilitate interaction among their component enhancers, the enhancers investigated here demonstrated functions that were largely additive. However, enhancers demonstrating autonomous activity strictly in one cell lineage, when missing, were found to significantly reduce output in the other thus revealing cryptic “stealth” activity. Further, Golli accumulation in all cell types investigated was markedly and uniformly attenuated by the absence of a key oligodendrocyte enhancer. Our observations expose a novel level of enhancer interaction and are consistent with a model in which enhancer-mediated DNA looping underlies higher-order Golli/Mbp regulatory organization.