Abstract
Histone deacetylases (HDACs) play crucial roles during mammalian development and for cellular homeostasis. In addition, these enzymes are promising targets for small molecule inhibitors in the treatment of cancer and neurological diseases. Conditional HDAC knock-out mice are excellent tools for defining the functions of individual HDACs in vivo and for identifying the molecular targets of HDAC inhibitors in disease. Here, we describe the generation of tissue-specific HDAC knock-out mice and delineate a strategy for the generation of conditional HDAC knock-in mice.
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References
Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10(1):32–42. doi:10.1038/nrg2485
Abel T, Zukin RS (2008) Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr Opin Pharmacol 8(1):57–64. doi:10.1016/j.coph.2007.12.002
Hagelkruys A, Sawicka A, Rennmayr M, Seiser C (2011) The biology of HDAC in cancer: the nuclear and epigenetic components. Handb Exp Pharmacol 206:13–37. doi:10.1007/978-3-642-21631-2_2
Kazantsev AG, Thompson LM (2008) Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Discov 7(10):854–868. doi:10.1038/nrd2681
Langley B, Gensert JM, Beal MF, Ratan RR (2005) Remodeling chromatin and stress resistance in the central nervous system: histone deacetylase inhibitors as novel and broadly effective neuroprotective agents. Curr Drug Targets CNS Neurol Disord 4(1):41–50
Reichert N, Choukrallah MA, Matthias P (2012) Multiple roles of class I HDACs in proliferation, differentiation, and development. Cell Mol Life Sci 69(13):2173–2187. doi:10.1007/s00018-012-0921-9
Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, Verdin E (2002) Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol Cell 9(1):45–57
Kelly RD, Cowley SM (2013) The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts. Biochem Soc Trans 41(3):741–749. doi:10.1042/BST20130010
Moser MA, Hagelkruys A, Seiser C (2014) Transcription and beyond: the role of mammalian class I lysine deacetylases. Chromosoma 123(1-2):67–78. doi:10.1007/s00412-013-0441-x
Dovey OM, Foster CT, Conte N, Edwards SA, Edwards JM, Singh R, Vassiliou G, Bradley A, Cowley SM (2013) Histone deacetylase (HDAC) 1 and 2 are essential for normal T cell development and genomic stability in mice. Blood 121(8):1335–1344. doi:10.1182/blood-2012-07-441949
Hagelkruys A, Lagger S, Krahmer J, Leopoldi A, Artaker M, Pusch O, Zezula J, Weissmann S, Xie Y, Schofer C, Schlederer M, Brosch G, Matthias P, Selfridge J, Lassmann H, Knoblich JA, Seiser C (2014) A single allele of Hdac2 but not Hdac1 is sufficient for normal mouse brain development in the absence of its paralog. Development 141(3):604–616. doi:10.1242/dev.100487
Winter M, Moser MA, Meunier D, Fischer C, Machat G, Mattes K, Lichtenberger BM, Brunmeir R, Weissmann S, Murko C, Humer C, Meischel T, Brosch G, Matthias P, Sibilia M, Seiser C (2013) Divergent roles of HDAC1 and HDAC2 in the regulation of epidermal development and tumorigenesis. EMBO J 32(24):3176–3191. doi:10.1038/emboj.2013.243
Zhang Y, Gilquin B, Khochbin S, Matthias P (2006) Two catalytic domains are required for protein deacetylation. J Biol Chem 281(5):2401–2404. doi:10.1074/jbc.C500241200
Hagelkruys A, Mattes K, Moos V, Rennmayr M, Ringbauer M, Sawicka A, Seiser C (2015) Essential non-redundant function of the catalytic activity of HDAC2 in mouse development. Mol Cell Biol 36:462–474. doi:10.1128/MCB.00639-15
Fu Y, Sander JD, Reyon D, Cascio VM, Joung JK (2014) Improving CRISPR-Cas nuclease specificity using truncated guide RNAs. Nat Biotechnol 32(3):279–284. doi:10.1038/nbt.2808
Zhang Z, Lutz B (2002) Cre recombinase-mediated inversion using lox66 and lox71: method to introduce conditional point mutations into the CREB-binding protein. Nucleic Acids Res 30(17), e90
Yang H, Wang H, Shivalila CS, Cheng AW, Shi L, Jaenisch R (2013) One-step generation of mice carrying reporter and conditional alleles by CRISPR/Cas-mediated genome engineering. Cell 154(6):1370–1379. doi:10.1016/j.cell.2013.08.022
Maruyama T, Dougan SK, Truttmann MC, Bilate AM, Ingram JR, Ploegh HL (2015) Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining. Nat Biotechnol 33(5):538–542. doi:10.1038/nbt.3190
Bonaparte D, Cinelli P, Douni E, Herault Y, Maas M, Pakarinen P, Poutanen M, Lafuente MS, Scavizzi F (2013) FELASA guidelines for the refinement of methods for genotyping genetically-modified rodents: a report of the Federation of European Laboratory Animal Science Associations Working Group. Lab Anim 47(3):134–145. doi:10.1177/0023677212473918
Ramirez A, Page A, Gandarillas A, Zanet J, Pibre S, Vidal M, Tusell L, Genesca A, Whitaker DA, Melton DW, Jorcano JL (2004) A keratin K5Cre transgenic line appropriate for tissue-specific or generalized Cre-mediated recombination. Genesis 39(1):52–57
Acknowledgments
We kindly thank Mircea Winter for providing the immunofluorescence and immunoblot figure. This work was supported by the Austrian Science Fund (P25807).
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Hagelkruys, A., Moser, M.A., Seiser, C. (2017). Generation of Tissue-Specific Mouse Models to Analyze HDAC Functions. In: Krämer, O. (eds) HDAC/HAT Function Assessment and Inhibitor Development. Methods in Molecular Biology, vol 1510. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6527-4_13
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DOI: https://doi.org/10.1007/978-1-4939-6527-4_13
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