Transcriptional repression

The core unit of the chromatin, the nucleosome, consists of histones arranged as an octamer consisting of a (H3/ H4)2-tetramer complexed with two histone H2A/H2B dimers. Accessibility to DNA-binding proteins (for replication, repair, or transcription) is achieved by posttranslational modifications of the amino-termini of the histones, the histone tails phosphorylation, acetylation, methylation, ubiquitination, and sumoyla-tion. Especially acetylation of histone tails has been linked to transcriptional activation, leading to weakened interaction of the core complexes with DNA and subsequently to decondensation of chromatin. In contrast, deacetylation leads to transcriptional repression. As mentioned above, transcriptional coactivators either possess HAT activity or recruit HATs. HDACs in turn act as corepressors. 

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Ding HF, Bustin M, Hansen U (1997) Alleviation of histone Hl-mediated transcriptional repression and chromatin compaction by the acidic activation region in chromosomal protein HMG-14. Mol Cell Biol 17 5843-5855... 

A system such as this can provide a powerful mechanism for transcriptional control. While bound to nucleosomes, PARP-1 promotes a transcriptionally repressed state, but one that is simultaneously poised for activation because of the allosteric activating effect of nucleosomes on PARP-1 enzymatic activity. In the presence of NAD+, PARP-1 can autoPARylate and release from nucleosomes, shifting the chromatin to a more transcriptionally active conformation. PARC can reset the system by cleaving the PAR chains from PARP-1, allowing PARP-1 to re-bind the nucleosomes and re-establish a transcriptionally repressed state. 

Doyen CM, An W, Angelov D, Bondarenko V, Mietton F, Studitsky VM, Hamiche A, Boeder RG, Bouvet P, Dimitrov S (2006) Mechanism of polymerase II transcription repression by the histone variant macroH2A. Mol Cell Biol 26 1156-1164... 

Girdwood D, Bumpass D, Vaughan OA, Thain A, Anderson LA, Snowden A W, Garcia-Wilson E, Perkins ND, Hay RT (2003) P300 transcriptional repression is mediated by SUMO modification. Mol Cell 11 1043-1054... 

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HD In Drosophila models of Huntington s disease, the HDAC inhibitors SAHA and sodium butyrate arrest the progressive neuronal degeneration and lethality (Steffan et al, 2001). SAHA and sodium butyrate have also been demonstrated to extend survival, ameliorate motor deficits and delay characteristic neuropathology in the mouse Huntington s disease model, R6/2 (Ferrante et al, 2003 Hockly et al, 2003). In NaBu-treated animals, animals displayed enhanced acetylation status of histones and pro-survival transcription factors like Spl and reduction in several neuropatho-logical hallmarks like striatal neuronal atrophy (Ferrante et al, 2003). Consistent with the idea that HDAC inhibition relieves transcriptional repression and that protection is downstream of mutant htt, neither SAHA nor sodium butyrate decreased mutant htt expression or aggregates (Ferrante et al, 2003 Hockly et al, 2003). 

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Stewart MD, Li J, Wong J (2005) Relationship between histone H3 lysine 9 methylation, transcription repression, and heterochromatin protein 1 recruitment. Mol Cell Biol 25 2525-2538... 

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Murphy M, Ahn J, Walker KK (1999) Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev 13 2490-2501 Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S (1998) FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res 241(1) 126-133 Nebbioso A, Clarke N, Voltz E, Germain E, Ambrosino C, Bontempo P, Alvarez R, Schiavone EM, Eerrara F, Bresciani F, Weisz A, de Lera AR, Gronemeyer H, Altucci L (2005) Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nature Med 11 77-84... 

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