Transcriptional Inhibition of Genes with Severe Histone H3 Hypoacetylation in the Coding Region

Kristjuhan, Arnold; Walker, Jane; Suka, Noriyuki; Grunstein, Michael; Roberts, Douglas; Cairns, Bradley R.; Svejstrup, Jesper Q.

doi:10.1016/s1097-2765(02)00647-0

Cited by 111 publications

(112 citation statements)

References 52 publications

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“…The decrease in H3 Lys-18 acetylation is quite dramatic, as indicated by Western blot analysis with an H3 Lys-18 acetylation-specific antibody. Histone hypoacetylation at promoters and coding regions of genes correlates with transcriptional repression (62). Severe histone global hypoacetylation in differentiated U937 cells suggests that transcription of the majority of genes is repressed, as underscored by the down-regulation of the transcription regulation molecules, including RNA polymerase II, FACT, and the RTF1-PAF complex, which are also ubiquitin ligases or their mediators needed for histone H2B ubiquitination (4 -8).…”

Section: Discussionmentioning

confidence: 99%

Mass Spectrometric Studies on Epigenetic Interaction Networks in Cell Differentiation

Xiong

Darwanto

Sharma

et al. 2011

Journal of Biological Chemistry

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Arrest of cell differentiation is one of the leading causes of leukemia and other cancers. Induction of cell differentiation using pharmaceutical agents has been clinically attempted for the treatment of these cancers. Epigenetic regulation may be one of the underlying molecular mechanisms controlling cell proliferation or differentiation. Here, we report on the use of proteomics-based differential protein expression analysis in conjunction with quantification of histone modifications to decipher the interconnections among epigenetic modifications, their modifying enzymes or mediators, and changes in the associated pathways/networks that occur during cell differentiation. During phorbol-12-myristate 13-acetate-induced differentiation of U937 cells, fatty acid synthesis and its metabolic processing, the clathrin-coated pit endocytosis pathway, and the ubiquitin/26 S proteasome degradation pathways were up-regulated. In addition, global histone H3/H4 acetylation and H2B ubiquitination were down-regulated concomitantly with impaired chromatin remodeling machinery, RNA polymerase II complexes, and DNA replication. Differential protein expression analysis established the networks linking histone hypoacetylation to the down-regulated expression/activity of p300 and linking histone H2B ubiquitination to the RNA polymerase II-associated FACT-RTF1-PAF1 complex. Collectively, our approach has provided an unprecedentedly systemic set of insights into the role of epigenetic regulation in leukemia cell differentiation.Both histone acetylation and H2B ubiquitination are associated with gene activation as defined by the "histone code" and "cross-talk" theories (1). As demonstrated previously in Berk's laboratory (2), small interfering RNA (siRNA)-mediated dual knockdown of CBP 5 and p300 resulted in specific histone H3Lys-18 hypoacetylation in vivo in both IMR90 and HeLa cells, indicating that p300/CBP, possibly together with their closely associated protein PCAF, are the major histone acetyltransferases required for maintaining global H3 Lys-18 acetylation.On the other hand, the putative histone H2B ubiquitination enzyme, UBCH6 (also known as UBE2E1), physically interacts with RNF20/40 (homologs of Bre1, the E3 ligase in yeast) and PAF1 to form a trimeric complex, which colocalizes with RNA polymerase II at transcriptionally active genes (3). RTF1, which has a function similar to Rad6 (mediates ubiquitination at lysine 123 of H2B in yeast) and is a component of the PAF1/RNA polymerase II complex, cooperatively interacts with RNF20/40, and FACT (facilitates chromatin transcription) to regulate H2B ubiquitination (4 -8).

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Section: Discussionmentioning

confidence: 99%

Mass Spectrometric Studies on Epigenetic Interaction Networks in Cell Differentiation

Xiong

Darwanto

Sharma

et al. 2011

Journal of Biological Chemistry

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“…In one case, TBP binding to chromatin-assembled SV40 minichromosomes was facilitated by histone acetylation at an underlying nucleosome (Sewack et al, 2001). However, in yeast gene systems, binding of TBP to promoters does not appear to strictly correlate with the acetylation status of promoter histones (Sekinger and Gross 2001;Katan-Khaykovich and Struhl 2002;Kristjuhan et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of MMTV transcription by HDAC inhibitors occurs independent of changes in chromatin remodeling and increased histone acetylation

2003

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Increased histone acetylation has been associated with activated gene transcription and decreased acetylation with repression. However, there is a growing number of genes known, which are downregulated by histone deacetylase (HDAC) inhibitors through unknown mechanisms. This study examines the mechanism by which the mouse mammary tumor virus (MMTV) promoter is repressed by the HDAC inhibitor, trichostatin A (TSA). We find that this repression is transcriptional in nature and that it occurs in the presence and absence of glucocorticoids. TSA decreases MMTV transcription at a rapid rate, reaching maximum in 30-60 min. In contrast with previous reports, the repression does not correlate with an inhibition of glucocorticoid-induced nuclease hypersensitivity or NF1-binding at the MMTV promoter. Surprisingly, TSA does not induce sizable increases in histone acetylation at the MMTV promoter nor does it inhibit histone deacetylation, which accompanies deactivation of the glucocorticoid-activated MMTV promoter. Repression of MMTV transcription by TSA does not depend on the chromatin organization of the promoter because a transiently transfected MMTV promoter construct with a disorganized nucleoprotein structure was also repressed by TSA treatment. Mutational analysis of the MMTV promoter indicates that repression by TSA is mediated through the TATA box region. These results suggest a novel mechanism that involves acetylation of nonhistone proteins necessary for basal transcription.

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“…ChIP assays were performed essentially as previously described (32). 4H8 (anti-Rpb1 antibody) was from Upstate Biotechnology (Lake Placid, NY), and the H3C antibody was a gift from Alain Verreault (Institute for Research in Immunology and Cancer, Montreal, QC, Canada).…”

Section: Methodsmentioning

confidence: 99%

A role for noncoding transcription in activation of the yeast PHO5 gene

Uhler

Hertel

Svejstrup

2007

Proc. Natl. Acad. Sci. U.S.A.

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148

151

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Noncoding, or intergenic, transcription by RNA polymerase II (RNA-PII) is remarkably widespread in eukaryotic organisms, but the effects of such transcription remain poorly understood. Here we show that noncoding transcription plays a role in activation, but not repression, of the Saccharomyces cerevisiae PHO5 gene. Histone eviction from the PHO5 promoter during activation occurs with normal kinetics even in the absence of the PHO5 TATA box, showing that transcription of the gene itself is not required for promoter remodeling. Nevertheless, we find that mutations that impair transcript elongation by RNAPII affect the kinetics of histone eviction from the PHO5 promoter. Most dramatically, inactivation of RNAPII itself abolishes eviction completely. Under repressing conditions, an Ϸ2.4-kb noncoding exosome-degraded transcript is detected that originates near the PHO5 termination site and is transcribed in the antisense direction. Abrogation of this transcript delays chromatin remodeling and subsequent RNAPII recruitment to PHO5 upon activation. We propose that noncoding transcription through positioned nucleosomes can enhance chromatin plasticity so that chromatin remodeling and activation of traversed genes occur in a timely manner.elongation ͉ intergenic transcription ͉ RNA polymerase II I n addition to transcribing all protein-encoding genes, RNA polymerase II (RNAPII) also transcribes a large group of less known and poorly understood untranslated RNAs. Recent genome-wide studies in several species reveal that such noncoding transcription is much more extensive than previously thought and that it occurs across intergenic regions, introns, and exons (see, for example, refs. 1 and 2). Recently, genome-wide studies in yeast have identified many cases of intergenic transcripts associated with promoters (3-5), raising the question of whether and how intergenic transcription across a promoter is used as a means of regulating that gene's transcription.During our studies on elongation and RNA processing factors in yeast, we discovered an intergenic transcript across the PHO5 promoter. This finding led us to investigate whether noncoding transcription might play a role in regulating this gene. PHO5 encodes an acid phosphatase that is regulated by phosphate availability (6). In high phosphate, four positioned nucleosomes are associated with the PHO5 promoter region (7). During phosphate starvation, the Pho4 activator translocates to the nucleus (8) and binds to PHO5 upstream activation sequences (UASp1 and UASp2) along with the Pho2 activator (9-11). This leads to eviction of the four positioned nucleosomes, making a 600-bp region effectively fully accessible (7,(12)(13)(14). Promoter remodeling is facilitated by, although not always absolutely dependent on, several transcription factor complexes including SAGA, Swi/Snf complex, INO80, and the Asf1 chaperone (14-18). High phosphate causes Pho4 accumulation in the cytoplasm, nucleosome reassembly on the promoter, and transcriptional repression of the gene.Here we show tha...

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Transcriptional Inhibition of Genes with Severe Histone H3 Hypoacetylation in the Coding Region

Cited by 111 publications

References 52 publications

Mass Spectrometric Studies on Epigenetic Interaction Networks in Cell Differentiation

Mass Spectrometric Studies on Epigenetic Interaction Networks in Cell Differentiation

Inhibition of MMTV transcription by HDAC inhibitors occurs independent of changes in chromatin remodeling and increased histone acetylation

A role for noncoding transcription in activation of the yeast PHO5 gene

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