@article{Inglese:2014rq,
	Abstract = {Copy number variation resulting in excess PMP22 protein causes the peripheral neuropathy, Charcot-Marie-Tooth Disease, type 1A.  To broadly interrogate chemically sensitive transcriptional pathways controlling PMP22 protein level, we used the targeting precision of TALEN-mediated genome editing to embed reporters within the genetic locus harboring the Peripheral Myelin Protein 22 (Pmp22) gene.  Using a Schwann cell line with constitutively high endogenous levels of Pmp22 we obtained monoallelic insertion of secreted bioluminescent reporters with sufficient signal to enable a 1536-well assay.  Our findings from the quantitative high-throughput screening (qHTS) of several thousand drugs and clinically investigated compounds using this assay design both overlapped and expanded results from a previous assay using a randomly inserted reporter gene controlled by a single regulatory element of the Pmp22 gene.  A key difference was the identification of a kinase-controlled inhibitory pathway of Pmp22 transcription revealed by the activity of the Protein kinase C (PKC)-modulator bryostatin},
	Author = {Inglese, J. and Dranchak, P. and Moran, P. and Jang, S.-W. and Cost, G.J. and Srinivasan, R. and Guha, R. and Martinez, N. and MacArthur, R. and Urnov, F.D. and Svaren, J.},
	Date-Added = {2014-06-24 19:24:45 +0000},
	Date-Modified = {2015-04-17 14:49:24 +0000},
	Journal = {{ACS} Chem.~Biol.},
	Number = {11},
	Pages = {2594--2602},
	Title = {Genome editing-enabled {HTS} assays expand drug target pathways for Charcot-Marie-Tooth disease},
	Volume = {9},
	Year = {2014},
	Bdsk-Url-1 = {http://dx.doi.org/10.1021/cb5005492}}

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To broadly interrogate chemically sensitive transcriptional pathways controlling PMP22 protein level, we used the targeting precision of TALEN-mediated genome editing to embed reporters within the genetic locus harboring the Peripheral Myelin Protein 22 (Pmp22) gene. Using a Schwann cell line with constitutively high endogenous levels of Pmp22 we obtained monoallelic insertion of secreted bioluminescent reporters with sufficient signal to enable a 1536-well assay. Our findings from the quantitative high-throughput screening (qHTS) of several thousand drugs and clinically investigated compounds using this assay design both overlapped and expanded results from a previous assay using a randomly inserted reporter gene controlled by a single regulatory element of the Pmp22 gene. 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To broadly interrogate chemically sensitive transcriptional pathways controlling PMP22 protein level, we used the targeting precision of TALEN-mediated genome editing to embed reporters within the genetic locus harboring the Peripheral Myelin Protein 22 (Pmp22) gene. Using a Schwann cell line with constitutively high endogenous levels of Pmp22 we obtained monoallelic insertion of secreted bioluminescent reporters with sufficient signal to enable a 1536-well assay. Our findings from the quantitative high-throughput screening (qHTS) of several thousand drugs and clinically investigated compounds using this assay design both overlapped and expanded results from a previous assay using a randomly inserted reporter gene controlled by a single regulatory element of the Pmp22 gene. 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