Functions of SAGA in development and disease

Wang, Li; Dent, Sharon Y.R.

doi:10.2217/epi.14.22

Cited by 116 publications

(94 citation statements)

References 97 publications

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“…It is possible that alteration in the post-translational modifications on GCN5, such as phosphorylation (28,36) or acetylation (28), could be responsible for the increased activity observed. GCN5 is part of the SAGA (Spt-Ada-Gcn5 acetyltransferase) and ATAC (Ada2a-containing) coactivator complexes (37). Thus, there is the alternative possibility that other proteins in the acetyltransferase complexes could undergo post-translational modification to alter the complex composition and increase GCN5 activity, as has been described earlier (38).…”

Section: Methionine Regulates Pgc-1␣ Activitymentioning

confidence: 89%

The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator

Tavares

Sharabi

Dominy

et al. 2016

Journal of Biological Chemistry

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Methionine is an essential sulfur amino acid that is engaged in key cellular functions such as protein synthesis and is a precursor for critical metabolites involved in maintaining cellular homeostasis. In mammals, in response to nutrient conditions, the liver plays a significant role in regulating methionine concentrations by altering its flux through the transmethylation, transsulfuration, and transamination metabolic pathways. A comprehensive understanding of how hepatic methionine metabolism intersects with other regulatory nutrient signaling and transcriptional events is, however, lacking. Here, we show that methionine and derived-sulfur metabolites in the transamination pathway activate the GCN5 acetyltransferase promoting acetylation of the transcriptional coactivator PGC-1␣ to control hepatic gluconeogenesis. Methionine was the only essential amino acid that rapidly induced PGC-1␣ acetylation through activating the GCN5 acetyltransferase. Experiments employing metabolic pathway intermediates revealed that methionine transamination, and not the transmethylation or transsulfuration pathways, contributed to methionine-induced PGC-1␣ acetylation. Moreover, aminooxyacetic acid, a transaminase inhibitor, was able to potently suppress PGC-1␣ acetylation stimulated by methionine, which was accompanied by predicted alterations in PGC-1␣-mediated gluconeogenic gene expression and glucose production in primary murine hepatocytes. Methionine administration in mice likewise induced hepatic PGC-1␣ acetylation, suppressed the gluconeogenic gene program, and lowered glycemia, indicating that a similar phenomenon occurs in vivo. These results highlight a communication between methionine metabolism and PGC-1␣-mediated hepatic gluconeogenesis, suggesting that influencing methionine metabolic flux has the potential to be therapeutically exploited for diabetes treatment.Amino acid sensing is a critical mechanism that cells employ to maintain homeostasis and enable survival upon fluctuations in the nutritional environment (1, 2). Despite variability in side chain chemical structure, cells are able to distinguish the distinct amino acids through the use of specific tRNAs. The amino acid protein sensor GCN2 detects deficiencies in amino acids in a tRNA-dependent manner and reprograms cellular metabolism to modulate energy consumption and maintain homeostasis (3, 4). Although mTORC1 is not considered to be a direct sensor of amino acid levels, it functions similarly to GCN2 to alter metabolic pathways in response to amino acid deprivation (5). Methionine, a dietary essential amino acid, is among the more toxic of the L-amino acids, and hence its abundance needs to be precisely regulated (6, 7). The liver is the primary organ concerned with the detoxification of methionine, and hence its ability to sense alterations in concentrations of this amino acid is vital (8). The existence of any cross-talk between hepatic methionine metabolism and other nutrient-regulated metabolic processes in the liver, such as glucose production, requi...

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Section: Methionine Regulates Pgc-1␣ Activitymentioning

confidence: 89%

The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator

Tavares

Sharabi

Dominy

et al. 2016

Journal of Biological Chemistry

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“…This complex shares the histonelike subunits TAF9, TAF10, and TAF12 with the transcription factor complex TFIID and contains a histone octamerlike structure [36]. TAF5L and TAF6L are also part of the PCAF complex [37]. All these TAFs and TAF variants were enriched in postmeiotic spermatids and might be part of both the PCAF and TFIID complexes.…”

Section: Discussionmentioning

confidence: 99%

Murine and Human Spermatids Are Characterized by Numerous, Newly Synthesized and Differentially Expressed Transcription Factors and Bromodomain-Containing Proteins

Klaus

Gonzalez

Bergmann

et al. 2016

Biology of Reproduction

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Much of spermatid differentiation takes place in the absence of active transcription, but in the early phase, large amounts of mRNA are synthesized, translationally repressed, and stored. Most nucleosomal histones are then degraded, and chromatin is repackaged by protamines. For both transcription and the histone-to-protamine transition in differentiating spermatids, chromatin must be opened. This raises the question of whether two different processes exist. It is conceivable that for initiation of the histone-to-protamine transition, the already accessible, actively transcribed chromatin regions are utilized or vice versa. We analyzed the enrichment of different canonical TATA-boxbinding, protein-associated factors and their variants in murine spermatids, diverse bromodomain-containing proteins, and components of the Polycomb repressive complexes PRC1 and PRC2 using quantitative PCR. We compared the enrichment of corresponding proteins in human and murine spermatids and analyzed the time frame of postmeiotic transcription and expression of histones, transition proteins, and protamines in human and murine spermatids using immunohistology. We correlated the expression of different transcription factors and bromodomain-containing proteins and the pattern of acetylated histones to active transcription and to the histone-to-protamine transition in both human and murine spermatids. Our findings suggest that differentiating spermatids use both common and specific features to open chromatin first for transcription and subsequently for histone-to-protamine transition.

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“…In yeast, Gcn5 was identified as the first transcription-related HAT (Brownell et al, 1996). Gcn5 is integrated into the SAGA (Spt-Ada-Gcn5 acetyltransferase) complex, which is an evolutionarily conserved transcriptional coactivator (Grant et al, 1997;Weake and Workman, 2012;Wang and Dent, 2014) that has several modules. The association of Gcn5 with the Ada proteins and Sgf29 in the complex enables Gcn5 to acetylate multiple lysine residues on nucleosomal histone H3 and is important for in vivo HAT activity (Grant et al, 1999;Balasubramanian et al, 2002;Bian et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Rice Homeodomain Protein WOX11 Recruits a Histone Acetyltransferase Complex to Establish Programs of Cell Proliferation of Crown Root Meristem

et al. 2017

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Shoot-borne crown roots are the major root system in cereals. Previous work has shown that the Wuschel-related homeobox gene WOX11 is necessary and sufficient to promote rice (Oryza sativa) crown root emergence and elongation. Here, we show that WOX11 recruits the ADA2-GCN5 histone acetyltransferase module to activate downstream target genes in crown root meristem. Rice ADA2 and GCN5 genes are highly expressed in root meristem and are shown to be essential for cell division and growth. WOX11 and ADA2-GCN5 commonly target and regulate a set of root-specific genes involved in energy metabolism, cell wall biosynthesis, and hormone response, some of which are known to be important for root development. The results indicate that the recruitment of ADA2-GCN5 by WOX11 establishes gene expression programs of crown root meristem cell division and suggest that permissive chromatin modification involving histone acetylation is a strategy for WOX11 to stimulate root meristem development.

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Functions of SAGA in development and disease

Cited by 116 publications

References 97 publications

The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator

The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator

Murine and Human Spermatids Are Characterized by Numerous, Newly Synthesized and Differentially Expressed Transcription Factors and Bromodomain-Containing Proteins

Rice Homeodomain Protein WOX11 Recruits a Histone Acetyltransferase Complex to Establish Programs of Cell Proliferation of Crown Root Meristem

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