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Nuc-ErbB3在周围神经髓鞘形成过程中通过调节H3K27me3水平和组蛋白甲基转移酶活性来建立表观遗传抑制。

Nuc-ErbB3 regulates H3K27me3 levels and HMT activity to establish epigenetic repression during peripheral myelination.

作者信息

Ness Jennifer K, Skiles Amanda A, Yap Eng-Hui, Fajardo Eduardo J, Fiser Andras, Tapinos Nikos

机构信息

Molecular Neuroscience and Neurooncology Laboratory, Geisinger Clinic, Danville, Pennsylvania.

Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York.

出版信息

Glia. 2016 Jun;64(6):977-92. doi: 10.1002/glia.22977. Epub 2016 Mar 28.

DOI:10.1002/glia.22977
PMID:27017927
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5021170/
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.

摘要

Nuc-ErbB3是来自ErbB3基因座的一种可变转录本，它与特定的DNA基序结合并与雪旺细胞染色质相关联。在此，我们构建了一种Nuc-ErbB3基因敲入小鼠，其细胞核中缺乏Nuc-ErbB3表达，而不影响神经调节蛋白-ErbB3受体信号传导。Nuc-ErbB3基因敲入小鼠在结旁区域表现出髓鞘过度形成和异常髓鞘形成。这种表型归因于Nuc-ErbB3缺失和组蛋白H3K27me3启动子占据后髓鞘形成相关基因转录的去抑制。Nuc-ErbB3基因敲入小鼠表现出H3K27me3与髓鞘形成相关基因启动子的结合减少，以及这些基因的RNA聚合酶II转录速率增加。此外，Nuc-ErbB3直接调节雪旺细胞中H3K27me3的水平。Nuc-ErbB3基因敲入小鼠表现出组蛋白H3K27me3甲基转移酶（HMT）活性显著降低和H3K27me3水平降低。总体而言，Nuc-ErbB3是一种主要的转录抑制因子，它在外周髓鞘形成过程中调节HMT活性，以在基因启动子上建立抑制性染色质景观。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/e5fce4a460c4/GLIA-64-977-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/8be55015435d/GLIA-64-977-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/31e61552b661/GLIA-64-977-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/306c98a3b45d/GLIA-64-977-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/d4579931a295/GLIA-64-977-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/dc072c5d809f/GLIA-64-977-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/e5fce4a460c4/GLIA-64-977-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/8be55015435d/GLIA-64-977-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/31e61552b661/GLIA-64-977-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/306c98a3b45d/GLIA-64-977-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/d4579931a295/GLIA-64-977-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/dc072c5d809f/GLIA-64-977-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1a3/5021170/e5fce4a460c4/GLIA-64-977-g006.jpg

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