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

English version

Autoři: Hooman Bagheri ^aff001; Hana Friedman ^aff001; Katherine A. Siminovitch ^aff002; Alan C. Peterson ^aff001
Působiště autorů: Department of Human Genetics, McGill University, Montreal, Quebec, Canada ^aff001; Department of Medicine, University of Toronto, Toronto, Ontario, Canada ^aff002; Department of Immunology, University of Toronto, Toronto, Ontario, Canada ^aff003; Mount Sinai Hospital, Lunenfeld-Tanenbaum and Toronto General Hospital Research Institutes, Toronto, Ontario, Canada ^aff004; Gerald Bronfman Department of Oncology, McGill University, Montréal, Québec, Canada ^aff005; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada ^aff006
Vyšlo v časopise: Transcriptional regulators of the Golli/myelin basic protein locus integrate additive and stealth activities. PLoS Genet 16(8): e32767. doi:10.1371/journal.pgen.1008752
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008752

Souhrn

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.

Klíčová slova:

Central nervous system – Chromatin – Messenger RNA – Sciatic nerves – Schwann cells – Spinal cord – Transcriptional control – Zygotes

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