Histone acetyltransferases

Histone acetyl transferases (HATs, EC 2.3.1.48 Table 5.1) catalyse the transfer of an acetyl group to the s-amino group of lysine residues in the tails and/or cores of histones, although, as for HDACs, some HATs also modify non-his-tone substrates e.g. transcription factors). HATs generally contain multiple subunits, and the functions of the catalytic subunit depend on the presence of other subunits. Domains that cooperate to recruit the HAT to the appropriate location in the genome include bromodomains, chromodomains, WD40 repeats, Tudor domains and PHD fingers.  

The gene specificity of HAT-mediated transcriptional activation is driven in part by the specificity of complex formation, and in part by specific cell signalling pathways. In addition, HATs acetylate other proteins including transcription factors, thereby playing a key role in complex regulatory networks. 

The potential clinical impact of HAT modulation covers a wide range of indications including cancer, HIV, diabetes mellitus, cardiac disease and neurodegeneration.  

Many HATs are involved in cancer pathogenesis and several are proposed as cancer biomarkers due to correlations of expression levels with outcomes, including a positive correlation between p300 expression levels and prostate cancer recurrence, and a negative correlation between hMOF and primary breast carcinomas. A series of isothiazolone PCAF-p300 inhibitors has shown inhibition of growth of a panel of colon and ovarian tumour cell lines.  

Subfamily HAT Knownjpreferred substrates Biological role Disease association 

Histone acetyltransferases (HATs) are enzymes that acetylate specific lysine residues in histones through the transfer of an acetyl group from an acetyl-coenzymeA (AcCoA) molecule, causing profound effects on chromatin structure and assembly as well as gene transcription. HATs are found in most, if not all, eukaryotic organisms as multiprotein complexes, some HAT catalytic subunits even being shared between various complexes that display different substrate specificities based on their subunit composition [12]. Despite their name, HATs do not restrict themselves to the acetylation of histones, since these enzymes have also been shown to act on nonhistone proteins, broadening their scope of action [13]. 

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Coactivators enhancing the transcriptional activity of steroid hormone receptors activators include SRC-1 (steroid-receptor co-activator 1) or TEF2 (transcriptional intermediary factor 2), which are recruited by the DNA/ steroid hormone receptor complex. Their main role is to attract other transcriptional coactivators with histone acetyltransferase activity in order to decondense chromatin and allow for the binding of components of the general transcription apparatus. 

Benkirane M, Chun RF, Xiao H, Ogryzko VV, Howard BH, Nakatani Y, Jeang KT (1998) Activation of integrated provirus requires histone acetyltransferase. p300 and P/CAF are coactivators for HIV-1 Tat. J Biol Chem 273(38) 24898-24905... 

Marzio G, Tyagi M, Gutierrez MI, Giacca M (1998) HIV-1 tat transactivator recruits p300 and CREB-binding protein histone acetyltransferases to the viral promoter. Proc Natl Acad Sd USA95(23) 13519-13524... 

Despite the complexity of the experiments and the enormous data manipulation necessary, complex biological pathways, as well as new drug targets are being identified by this method. Examples include screens for compounds that arrest cells in mitosis, that block cell migration, and that block the secretory pathway [50], or assays with primary T cells from PLP TCR transgenic mice for their inhibitory activity on the proliferation and secretion of proinflammatory cytokines in PLP-reactive T cells [51], and identification of small-molecule inhibitors of histone acetyltransferase activity [52]. 

HeLa histone acetyltransferase Ammonium acetate Triphasic LCQ DECA SEQUEST (Cai et al., 2005)... 

Fig. 10.2. FSPIM analysis of the interaction between maize transcriptional coactivators—GCN5 and ADA2—fused to CFP and YFP. GCN5 is a histone acetyltransferase that, in conjunction with adaptor protein ADA2, modulates transcription in diverse eukaryotes by affecting the acetylation status of the core histones in nucleosomes [63]. CFP- and YFP-tagged proteins, expressed in protoplasts, were excited by the 458 nm and the 514 nm laser lines sequentially. CFP fluorescence was selectively detected by an FIFT 458 dichroic mirror and BP 470-500 band pass emission filter while YFP fluorescence was selectively detected by using an HFT 514 dichroic mirror and...

Cao, X. and Sudhof, T. C. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293 115-120, 2001. 

The structure of the chromatin and their state of acetylation are important at the moment of initiating the gene transcription. Indeed, some of the transcription factors recruited by the receptor dimer have histone-acetyltransferase activity that permits the gene transcription after diminishing the condensation of the chromatin (Gruber et al. 2002 Nilsson et al. 2001 Vigushin et al. 2002). 

One of the most-studied covalent modifications is the acetylation of the lysine residues of histone tails. The acetylation state of lysines of nucleosomal histones modulates chromatin structure and regulates gene transcriptional activity. The balance of lysine acetylation is controlled by the antagonistic action of two enzyme families histone deacetylases (HDACs) and histone acetyltransferases (HATs). In humans there are essentially three main HDAC subclasses [6]. 

Ogryzko VV, Schiltz RE, Russanova V, Howard BH, Nakatani Y (1996) The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87 953-959 Okada M, Cheeseman IM, Hori T, Okawa K, McLeod IX, Yates JR, 3rd, Desai A, Fukagawa T (2006) The CENP-H-1 complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres. Nat Cell Biol 8 446-457... 

Qin S, Parthun MR (2006) Recruitment of the type B histone acetyltransferase Hatlp to chromatin is linked to DNA double-strand breaks. Mol.Cell.Biol 26 3649-3658... 

ABERRANT FORMS OF HISTONE ACETYLTRANSFERASES IN HUMAN DISEASE... 

Abbreviations CBP, CREB binding protein CREB, cAMP response element binding protein FAT, factor acetyltransferase HAT, histone acetyltransferase MEL, mixed lineage leukaemia protein MORE, MOZ related factor MOZ, monocytic leukaemia zinc finger protein PHD, plant homeodomain RTS, Rubinstein-Taybi syndrome, TIE, transcription intermediary factor... 

Aberrant Forms of Histone Acetyltransferases in Human Disease... 

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