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Drug-induced loss of imprinting revealed using bioluminescent reporters of Cdkn1c.

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Dimond, Andrew 
Van de Pette, Mathew 
Taylor-Bateman, Victoria 
Brown, Karen 
Sardini, Alessandro 


Genomic imprinting is an epigenetically mediated mechanism that regulates allelic expression of genes based upon parent-of-origin and provides a paradigm for studying epigenetic silencing and release. Here, bioluminescent reporters for the maternally-expressed imprinted gene Cdkn1c are used to examine the capacity of chromatin-modifying drugs to reverse paternal Cdkn1c silencing. Exposure of reporter mouse embryonic stem cells (mESCs) to 5-Azacytidine, HDAC inhibitors, BET inhibitors or GSK-J4 (KDM6A/B inhibitor) relieved repression of paternal Cdkn1c, either selectively or by inducing biallelic effects. Treatment of reporter fibroblasts with HDAC inhibitors or GSK-J4 resulted in similar paternal Cdkn1c activation, whereas BET inhibitor-induced loss of imprinting was specific to mESCs. Changes in allelic expression were generally not sustained in dividing cultures upon drug removal, indicating that the underlying epigenetic memory of silencing was maintained. In contrast, Cdkn1c de-repression by GSK-J4 was retained in both mESCs and fibroblasts following inhibitor removal, although this impact may be linked to cellular stress and DNA damage. Taken together, these data introduce bioluminescent reporter cells as tools for studying epigenetic silencing and disruption, and demonstrate that Cdkn1c imprinting requires distinct and cell-type specific chromatin features and modifying enzymes to enact and propagate a memory of silencing.


Acknowledgements: We thank GlaxoSmithKline for gifting inhibitor compounds for use in this study. This work was supported by funding from the Medical Research Council (MC_U120027516, MC_UP_1605/12 and MC_UP_1605/11) as well as awards from the Wellcome Trust (099276/Z/12/Z to M.M. and ISSF PS3125_WCMA to M.V.P.). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.


Animals, Mice, DNA Methylation, Histone Deacetylase Inhibitors, Genomic Imprinting, Epigenesis, Genetic, Chromatin, Cyclin-Dependent Kinase Inhibitor p57

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Springer Science and Business Media LLC
Wellcome Trust (PS3125_WCMA, 099276/Z/12/Z)
Medical Research Council (MC_U120027516)