PMID- 24105466 OWN - NLM STAT- MEDLINE DCOM- 20140909 LR - 20211021 IS - 1460-2083 (Electronic) IS - 0964-6906 (Print) IS - 0964-6906 (Linking) VI - 23 IP - 4 DP - 2014 Feb 15 TI - MeCP2: a novel Huntingtin interactor. PG - 1036-44 LID - 10.1093/hmg/ddt499 [doi] AB - Transcriptional dysregulation has been proposed to play a major role in the pathology of Huntington's disease (HD). However, the mechanisms that cause selective downregulation of target genes remain unknown. Previous studies have shown that mutant huntingtin (Htt) protein interacts with a number of transcription factors thereby altering transcription. Here we report that Htt directly interacts with methyl-CpG binding protein 2 (MeCP2) in mouse and cellular models of HD using complimentary biochemical and Fluorescent Lifetime Imaging to measure Forster Resonance Energy Transfer approaches. Htt-MeCP2 interactions are enhanced in the presence of the expanded polyglutamine (polyQ) tract and are stronger in the nucleus compared with the cytoplasm. Furthermore, we find increased binding of MeCP2 to the promoter of brain-derived neurotrophic factor (BDNF), a gene that is downregulated in HD, in the presence of mutant Htt. Finally, decreasing MeCP2 levels in mutant Htt-expressing cells using siRNA increases BDNF levels, suggesting that MeCP2 downregulates BDNF expression in HD. Taken together, these findings suggest that aberrant interactions between Htt and MeCP2 contribute to transcriptional dysregulation in HD. FAU - McFarland, Karen N AU - McFarland KN AD - Department of Neurology and The McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA. FAU - Huizenga, Megan N AU - Huizenga MN FAU - Darnell, Shayna B AU - Darnell SB FAU - Sangrey, Gavin R AU - Sangrey GR FAU - Berezovska, Oksana AU - Berezovska O FAU - Cha, Jang-Ho J AU - Cha JH FAU - Outeiro, Tiago F AU - Outeiro TF FAU - Sadri-Vakili, Ghazaleh AU - Sadri-Vakili G LA - eng GR - AG15379/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20131008 PL - England TA - Hum Mol Genet JT - Human molecular genetics JID - 9208958 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Htt protein, mouse) RN - 0 (Huntingtin Protein) RN - 0 (Mecp2 protein, mouse) RN - 0 (Methyl-CpG-Binding Protein 2) RN - 0 (Nerve Tissue Proteins) RN - 0 (Nuclear Proteins) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/genetics/metabolism MH - Cell Line MH - Corpus Striatum/metabolism MH - Down-Regulation MH - Gene Expression MH - Humans MH - Huntingtin Protein MH - Huntington Disease/metabolism MH - Methyl-CpG-Binding Protein 2/*metabolism MH - Mice MH - Mice, Transgenic MH - Nerve Tissue Proteins/*metabolism MH - Nuclear Proteins/*metabolism MH - Promoter Regions, Genetic MH - Protein Interaction Mapping MH - Transcription, Genetic PMC - PMC3900110 EDAT- 2013/10/10 06:00 MHDA- 2014/09/10 06:00 PMCR- 2015/02/15 CRDT- 2013/10/10 06:00 PHST- 2013/10/10 06:00 [entrez] PHST- 2013/10/10 06:00 [pubmed] PHST- 2014/09/10 06:00 [medline] PHST- 2015/02/15 00:00 [pmc-release] AID - ddt499 [pii] AID - 10.1093/hmg/ddt499 [doi] PST - ppublish SO - Hum Mol Genet. 2014 Feb 15;23(4):1036-44. doi: 10.1093/hmg/ddt499. Epub 2013 Oct 8.