Description
Histones, nuclear proteins that bind DNA and form nucleosomes, are directly involved with both the packaging of DNA into chromosomes and the regulation of transcription. Histone acetylation/deacetylation is a major factor in regulating chromatin structural dynamics during transcription (Bauer et al., 1994; Lee et al., 1993).
Gene Function
Taunton et al. (1996) stressed the important role of histone deacetylation in transcriptional regulation and cell cycle progression. Wolffe (1996) reviewed the findings in light of recent literature.
RB
The tumor suppressor protein RB1 (614041) inhibits cell proliferation by repressing a subset of genes that are controlled by the E2F family of transcription factors and are involved in progression from the G1 to the S phase of the cell cycle. RB1, which is recruited to target promoters by E2F1 (189971), represses transcription by masking the E2F1 transactivation domain and by inhibiting surrounding enhancer elements, an active repression that may be crucial for the proper control of progression through the cell cycle. Some transcriptional regulators act by acetylating or deacetylating the tails protruding from the core histones, thereby modulating the local structure of chromatin; for example, some transcriptional repressors function through the recruitment of histone deacetylases. Magnaghi-Jaulin et al. (1998) showed that the histone deacetylase HDAC1 physically interacts and cooperates with RB1. In HDAC1, the sequence involved is an LXCXE motif, similar to that used by viral transforming proteins to contact RB1. The results strongly suggested that the RB1/HDAC1 complex is a key element in the control of cell proliferation and differentiation and that it is a likely target for transforming viruses.
p53
The p53 tumor suppressor (191170) is a transcriptional factor whose activity is modulated by protein stability and posttranslational modifications including acetylation. Luo et al. (2000) showed that deacetylation of p53 is mediated by a HDAC1-containing complex. They also purified a p53 target protein, which they named PID, in the deacetylase complexes. PID is identical to metastasis-associated protein-2 (MTA2, or MTA1L1; 603947), which had been identified as a component of the nucleosome remodeling and histone deacetylation (NURD) complex. The authors found that MTA1L1 specifically interacts with p53 both in vitro and in vivo, and its expression reduces significantly the steady-state levels of acetylated p53. MTA1L1 expression strongly represses p53-dependent transcriptional activation, and, notably, it modulates p53-mediated cell growth arrest and apoptosis. Luo et al. (2000) concluded that their results show that deacetylation and functional interactions between the MTA1L1-associated NURD complex may represent an important pathway to regulate p53 function.
The histone deacetylase complex, conserved among eukaryotic organisms, includes SAP30 (603378), SIN3 (see 607776), SAP18 (602949), the histone deacetylases HDAC1 and HDAC2 (605164), the histone-binding proteins RbAp46 (RBBP7; 300825) and RbAp48 (RBBP4; 602923), as well as other polypeptides (Zhang et al., 1998). Lin et al. (1998) reported that the association of PLZF-RAR-alpha (see 176797) and PML-RAR-alpha (see 102578) with the histone deacetylase complex helps to determine both the development of acute promyelocytic leukemia (APL; 612376) and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of retinoic acid-sensitive, and restore retinoid responses of retinoic acid-resistant, APL cell lines. Lin et al. (1998) concluded that oncogenic retinoic acid receptors mediate leukemogenesis through aberrant chromatin acetylation, and that pharmacologic manipulation of nuclear receptor cofactors may be a useful approach in the treatment of human disease.
Grignani et al. (1998) demonstrated that both PML-RAR-alpha and PLZF-RAR-alpha fusion proteins recruit the nuclear corepressor (NCOR; see 600849)-histone deacetylase complex through the RAR-alpha CoR box. PLZF-RAR-alpha contains a second, retinoic acid-resistant binding site in the PLZF amino-terminal region. High doses of retinoic acid release histone deacetylase activity from PML-RAR-alpha, but not from PLZF-RAR-alpha. Mutation of the NCOR binding site abolishes the ability of PML-RAR-alpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biologic effects of PLZF-RAR-alpha from being an inhibitor to an activator of the retinoic acid signaling pathway. Therefore, Grignani et al. (1998) concluded that recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of retinoic acid on the stability of the PML-RAR-alpha and PLZF-RAR-alpha corepressor complexes determines the differential response of APLs to retinoic acid.
Wade (2001) reviewed the role of histone deacetylases in transcriptional and G1 checkpoint control, as well as their altered activity in malignant states.
Zhong et al. (2002) demonstrated that transcriptionally inactive nuclear NFKB in resting cells consists of homodimers of either p65 (164014) or p50 (164011) complexed with the histone deacetylase HDAC1. Only the p50-HDAC1 complexes bound to DNA and suppressed NFKB-dependent gene expression in unstimulated cells. Appropriate stimulation caused nuclear localization of NFKB complexes containing phosphorylated p65 that associated with CBP (600140) and displaced the p50-HDAC1 complexes. These results demonstrated that phosphorylation of p65 determines whether it associates with either CBP or HDAC1, ensuring that only p65 entering the nucleus from cytoplasmic NFKB-IKB (164008) complexes can activate transcription.
Rogina et al. (2002) found that Drosophila males heterozygous for either a hypomorphic or null mutation of RPD3 have life span extension of 33% and 41 to 47%, respectively. Females heterozygous for the hypomorphic allele had a 52% increase in life span, whereas females carrying the null mutation had only modest changes in life span (maximum but not median life spans were increased). Rogina et al. (2002) found that under their 2 life-extending conditions, Rpd3 mutants fed normal food and wildtype flies fed low calorie food, Sir2 (see 604480) expression was increased 2-fold. They concluded that their results highlighted the conservation of longevity regulation across distant species boundaries and suggested a genetic pathway that begins with caloric restriction and proceeds to downregulation of RPD3, followed by SIR2-independent regulation of longevity effector genes and/or increased SIR2 levels and SIR2-dependent modulation of longevity effector genes.
Hakimi et al. (2003) identified a family of multiprotein corepressor complexes that function through modifying chromatin structure to keep genes silent. The polypeptide composition of these complexes includes a common core of 2 subunits, HDAC1/HDAC2 and the FAD-binding protein BHC110 (KDM1A; 609132). Other subunits of these complexes include ZNF261 (300061), GTF2I (601679), and polypeptides associated with cancer-causing chromosomal translocations.
Nusinzon and Horvath (2003) found that inhibition of HDAC1 by pharmacologic means or RNA interference inhibited IFNA (147660)-induced transcriptional and antiviral responses. EMSA and fluorescence microscopy demonstrated that HDAC1 inhibition had no impact on STAT1 (600555) and STAT2 (600556) activation, dimerization, nuclear translocation, and DNA binding activity. ChIP analysis showed that IFNA stimulation caused reduced acetylated histone H4 levels in the ISG54 locus. Immunoblot analysis revealed that HDAC1, but not HDAC4 (605314) or HDAC5 (605315), associated with both STAT1 and STAT2. Modulation of HDAC1 levels suggested that HDAC1 is a critical positive coactivator for ISGF3 (147574)-dependent transcriptional responses. Nusinzon and Horvath (2003) concluded that HDAC1 is an essential element of the coactivation system for IFN-induced gene regulation and antiviral responses.
T-cell lymphomas lose expression of SHP1 (PTPN6; 176883) due to DNA methylation of its promoter. Zhang et al. (2005) demonstrated that malignant T cells expressed DNMT1 (126375) and that STAT3 (102582) could bind sites in the SHP1 promoter in vitro. STAT3, DNMT1, and HDAC1 formed complexes and bound to the SHP1 promoter in vivo. Antisense DNMT1 and STAT3 siRNA induced DNA demethylation in malignant T cells and expression of SHP1. Zhang et al. (2005) concluded that STAT3 may transform cells by inducing epigenetic silencing of SHP1 in cooperation with DNMT1 and HDAC1.
Although HDACs are generally viewed as corepressors, Qiu et al. (2006) showed that Hdac1 served as a coactivator for glucocorticoid receptor (GCCR; 138040) in mouse cells. Hdac1 was acetylated after association with Gccr, and this acetylation event correlated with a decrease in promoter activity. Hdac1 in repressed chromatin was highly acetylated, whereas Hdac1 on transcriptionally active chromatin showed a low level of acetylation. Acetylation of purified Hdac1 inactivated its deacetylase activity, and mutation of the critical acetylation sites abrogated Hdac1 function in vivo.
A transcriptional corepressor complex containing LSD1 (KDM1A), COREST (RCOR; 607675), and HDAC1 represses transcription by removing histone modifications associated with transcriptional activation. Gocke and Yu (2008) found that ZNF198 (ZMYM2; 602221) and REST (600571) interacted with LSD1/COREST/HDAC1 in a mutually exclusive manner in human cell lines. ZNF198 was required for repression of E-cadherin (CDH1; 192090), but not REST-responsive genes. ZNF198 interacted with chromatin and stabilized the LSD1/COREST/HDAC1 complex on chromatin. The MYM domain of ZNF198 mediated interaction of ZNF198 with LSD1/COREST/HDAC1. Sumoylation of HDAC1 by SUMO2 (603042) enhanced its binding to ZNF198 via a noncovalent mechanism, but it also weakened the interaction between HDAC1 and COREST.
Hait et al. (2009) found that sphingosine kinase-2 (SPHK2; 607092), one of the isoenzymes that generates S1P, was associated with histone H3 and produced S1P that regulated histone acetylation. S1P specifically bound to the histone deacetylases HDAC1 and HDAC2 (605164) and inhibited their enzymatic activity, preventing the removal of acetyl groups from lysine residues within histone tails. SPHK2 associated with HDAC1 and HDAC2 in repressor complexes and was selectively enriched at the promoters of the genes encoding the cyclin-dependent kinase inhibitor p21 (116899) or the transcriptional regulator c-fos (164810), where it enhanced local histone H3 acetylation and transcription. Thus, Hait et al. (2009) concluded that HDACs are direct intracellular targets of S1P and link nuclear S1P to epigenetic regulation of gene expression.
MicroRNAs (miRNAs) are small noncoding RNAs that downregulate gene expression by binding to complementary sequences in the 3-prime UTRs of target mRNAs. Using in silico analysis, Noonan et al. (2009) identified target sequences for miRNA449A (MIR449A; 613131) in the 3-prime UTRs of a number of genes involved in cell cycle regulation, including HDAC1. Use of the HDAC1 3-prime UTR in a reporter gene assay established that HDAC1 is a direct target of MIR449A. Furthermore, Noonan et al. (2009) demonstrated that MIR449A regulated cell growth and viability of prostate cancer cells in part by repressing expression of HDAC1.
Robert et al. (2011) showed that HDAC inhibition/ablation specifically counteracts yeast Mec1 (ortholog of human ATR, 601215) activation, double-strand break processing, and single-strand DNA-RFA nucleofilament formation. Moreover, the recombination protein Sae2 (human CTIP; 604124) is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 (see HDAC4) and Rpd3 (HDAC1), and 1 histone acetyltransferase (HAT), Gcn5 (GCN5L2; 602301), have key roles in these processes. Robert et al. (2011) also found that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of Hda1 and Rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor (MTOR; 601231), also causes Sae2 degradation. Robert et al. (2011) proposed that Rpd3, Hda1, and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand break processing with autophagy.
Lin et al. (2012) dissected the functional specificity of 12 critical human lysine deacetylases using a genomewide synthetic lethality screen in cultured human cells. The genetic interaction profiles revealed enzyme-substrate relationships between individual lysine deacetylases and many important substrates governing a wide array of biologic processes including metabolism, development, and cell cycle progression. Lin et al. (2012) further confirmed that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), PRKAA1 (602739), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 and p300 (602700). Deacetylation of AMPK enhanced physical interaction with the upstream kinase LKB1 (602216), leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. Lin et al. (2012) concluded that their findings provided insights into underappreciated metabolic regulatory roles of HDAC1 in coordinating nutrient availability and cellular responses upstream of AMPK, and demonstrated the importance of high-throughput genetic interaction profiling to elucidate functional specificity and critical substrates of individual human lysine deacetylases potentially valuable for therapeutic applications.
