Regulation of the neuropathy-associated Pmp22 gene by a distal super-enhancer

Human Molecular Genetics
Harrison PanteraJohn Svaren

Abstract

Peripheral nerve myelination is adversely affected in the most common form of the hereditary peripheral neuropathy called Charcot-Marie-Tooth Disease. This form, classified as CMT1A, is caused by a 1.4 Mb duplication on chromosome 17, which includes the abundantly expressed Schwann cell myelin gene, Peripheral Myelin Protein 22 (PMP22). This is one of the most common copy number variants causing neurological disease. Overexpression of Pmp22 in rodent models recapitulates several aspects of neuropathy, and reduction of Pmp22 in such models results in amelioration of the neuropathy phenotype. Recently we identified a potential super-enhancer approximately 90-130 kb upstream of the Pmp22 transcription start sites. This super-enhancer encompasses a cluster of individual enhancers that have the acetylated histone H3K27 active enhancer mark, and coincides with smaller duplications identified in patients with milder CMT1A-like symptoms, where the PMP22 coding region itself was not part of the duplication. In this study, we have utilized genome editing to create a deletion of this super-enhancer to determine its role in Pmp22 regulation. Our data show a significant decrease in Pmp22 transcript expression using allele-specific internal ...Continue Reading

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Citations

May 2, 2020·Human Molecular Genetics·Harrison PanteraJohn Svaren
Jul 7, 2020·Experimental Neurobiology·Rajarathinam ThenmozhiYoung Bin Hong
Jul 11, 2020·The Journal of Biological Chemistry·Justin T MarinkoCharles R Sanders
Oct 7, 2018·Journal of Mammary Gland Biology and Neoplasia·Kyung Hyun YooHa Youn Shin
Oct 7, 2019·Brain Research·Harrison PanteraJohn Svaren
Nov 30, 2020·Neuroscience Letters·Marina StavrouKleopas A Kleopa
Jul 3, 2021·International Journal of Molecular Sciences·Marina StavrouKleopas A Kleopa

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