Transcriptional regulators of the Golli/myelin basic protein locus integrate additive and stealth activities

Abstract

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.

Increased Expression of VCAM1 on Brain Endothelial Cells Drives Blood–Brain Barrier Impairment Following Chronic Cerebral Hypoperfusion

“…Comparable findings were also documented in other white matter regions (Figure S3). Myelin basic protein (MBP) serves as a marker of the myelin sheath surrounding neuronal axons . Immunofluorescence staining showed a gradual decrease in the density of MBP in each white matter region from 14 to 28 days following CCH (Figure S4A,C–E).…”

Impact of airborne total suspended particles (TSP) and fine particulate matter (PM2.5)‐induced developmental toxicity in zebrafish (Danio rerio) embryos

“…To further understand the neurodevelopmental toxicity evinced by TSP and PM 2.5 in zebrafish embryos/larvae, gene expression profiling patterns involved in CNS development such as mbp , gfap , α1‐tubulin , elavl3 , neurog1 , and shha were studied. Myelin basic protein (MBP), a structural component of myelin sheath, is involved in the formation and stabilization of the myelin membrane, promoting tubulin assembly into microtubules for cell morphogenesis in different stages of oligodendroglial development (Bagheri et al, 2020). A marked decrease in the mbp gene expression in TSP as well as PM 2.5 ‐exposed groups might disrupt myelination and damage neuronal functions (Brösamle & Halpern, 2002).…”

Identification of Myelin Basic Protein Proximity Interactome Using TurboID Labeling Proteomics

“…Myelin basic protein (MBP) is an important structural unit of the myelin sheath of axons and is associated with many neurodegenerative diseases, in particular, multiple sclerosis (MS) [ 1 , 2 , 3 ]. MS is an autoimmune, multifactorial, demyelinating and neurodegenerative disease of unknown pathogenesis [ 4 ].…”