title: Nuc-ErbB3 regulates H3K27me3 levels and HMT activity to establish epigenetic repression during peripheral myelination.
abstract: Nuc-ErbB3 an alternative transcript from the ErbB3 locus binds to a specific DNA motif and associates with Schwann cell chromatin. Here we generated a nuc-ErbB3 knockin mouse that lacks nuc-ErbB3 expression in the nucleus without affecting the neuregulin-ErbB3 receptor signaling. Nuc-ErbB3 knockin mice exhibit hypermyelination and aberrant myelination at the paranodal region. This phenotype is attributed to de-repression of myelination associated gene transcription following loss of nuc-ErbB3 and histone H3K27me3 promoter occupancy. Nuc-ErbB3 knockin mice exhibit reduced association of H3K27me3 with myelination-associated gene promoters and increased RNA Pol-II rate of transcription of these genes. In addition, nuc-ErbB3 directly regulates levels of H3K27me3 in Schwann cells. Nuc-ErbB3 knockin mice exhibit significant decrease of histone H3K27me3 methyltransferase (HMT) activity and reduced levels of H3K27me3. Collectively, nuc-ErbB3 is a master transcriptional repressor, which regulates HMT activity to establish a repressive chromatin landscape on promoters of genes during peripheral myelination.
authors.affiliation: Molecular Neuroscience and Neurooncology Laboratory, Geisinger Clinic, Danville, Pennsylvania.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Ness
authors.affiliation: Molecular Neuroscience and Neurooncology Laboratory, Geisinger Clinic, Danville, Pennsylvania.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Skiles
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Eng-Hui
authors.initials: EH
authors.lastname: Yap
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Fajardo
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Andras
authors.initials: A
authors.lastname: Fiser
authors.affiliation: Molecular Neuroscience and Neurooncology Laboratory, Geisinger Clinic, Danville, Pennsylvania.
authors.forename: Nikos
authors.initials: N
authors.lastname: Tapinos
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D063185:Epigenetic Repression / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D020880:Neuregulins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D020880:Neuregulins; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; C000607800:ErbB3 protein, mouse; D020893:Receptor, ErbB-3
keywords: PNS myelination; chromatin; transcriptional repression