MYC interacts with the human STAGA coactivator complex via multivalent contacts with the GCN5 and TRRAP subunits

Zhang, Na; Ichikawa, Wataru; Faiola, Francesco; Lo, Szuying; Liu, Xiaohui; Martinez, Ernest

doi:10.1016/j.bbagrm.2014.03.017

Cited by 44 publications

(33 citation statements)

References 62 publications

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“…A more recent study concluded that global amplification of gene expression might be secondary to the effects of Myc in regulating specific gene targets, especially those related to cell growth and division (Sabo et al 2014). Our data are consistent with previous studies that indicated a role for Myc and E2f1 in SAGA complex recruitment to specific target genes in transformed cells (McMahon et al 1998(McMahon et al , 2000Zhang et al 2014). Furthermore, Myc facilitates global maintenance of active acetylated chromatin and recruits Gcn5 to cell cycle-related genes in neural stem cells (Knoepfler et al 2006;Martinez-Cerdeno et al 2012).…”

Section: Discussionsupporting

confidence: 82%

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Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming

et al. 2015

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Embryonic stem cells are maintained in a self-renewing and pluripotent state by multiple regulatory pathways. Pluripotent-specific transcriptional networks are sequentially reactivated as somatic cells reprogram to achieve pluripotency. How epigenetic regulators modulate this process and contribute to somatic cell reprogramming is not clear. Here we performed a functional RNAi screen to identify the earliest epigenetic regulators required for reprogramming. We identified components of the SAGA histone acetyltransferase complex, in particular Gcn5, as critical regulators of reprogramming initiation. Furthermore, we showed in mouse pluripotent stem cells that Gcn5 strongly associates with Myc and that, upon initiation of somatic reprogramming, Gcn5 and Myc form a positive feed-forward loop that activates a distinct alternative splicing network and the early acquisition of pluripotency-associated splicing events. These studies expose a Myc-SAGA pathway that drives expression of an essential alternative splicing regulatory network during somatic cell reprogramming.

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Section: Discussionsupporting

confidence: 82%

“…However, recruitment of the SAGA complex with an intact HAT module appears to be key. Trrap and Gcn5 have both been reported to interact directly with Myc (McMahon et al 1998Zhang et al 2014), consistent with our findings (Supplemental Fig. S5B), so these factors likely negotiate recruitment of the SAGA complex to Myc target genes.…”

Section: Discussionsupporting

confidence: 81%

Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming

et al. 2015

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“…These functions include regulating ribosomal protein gene expression and cell growth . Importantly, mammalian TRRAP interacts with and is required for the activity of Myc . These results delineate a link between Myc and TRRAP that is reminiscent of the Sfp1/Tra1 connection observed in yeast.…”

Section: Discussionmentioning

confidence: 65%

Sfp1 links TORC1 and cell growth regulation to the yeast SAGA‐complex component Tra1 in response to polyQ proteotoxicity

Jiang

Berg

Genereaux

et al. 2019

Traffic

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Chromatin remodeling regulates gene expression in response to the accumulation of misfolded polyQ proteins associated with Huntington's disease (HD). Tra1 is an essential component of both the SAGA/SLIK and NuA4 transcription co‐activator complexes and is linked to multiple cellular processes, including protein trafficking and signaling pathways associated with misfolded protein stress. Cells with compromised Tra1 activity display phenotypes distinct from deletions encoding components of the SAGA and NuA4 complexes, indicating a potentially unique regulatory role of Tra1 in the cellular response to protein misfolding. Here, we employed a yeast model to define how the expression of toxic polyQ expansion proteins affects Tra1 expression and function. Expression of expanded polyQ proteins mimics deletion of SAGA/NuA4 components and results in growth defects under stress conditions. Moreover, deleting genes encoding SAGA and, to a lesser extent, NuA4 components exacerbates polyQ toxicity. Also, cells carrying a mutant Tra1 allele displayed increased sensitivity to polyQ toxicity. Interestingly, expression of polyQ proteins upregulated the expression of TRA1 and other genes encoding SAGA components, revealing a feedback mechanism aimed at maintaining Tra1 and SAGA functional integrity. Moreover, deleting the TORC1 (Target of Rapamycin) effector SFP1 abolished upregulation of TRA1 upon expression of polyQ proteins. While Sfp1 is known to adjust ribosome biogenesis and cell size in response to stress, we identified a new role for Sfp1 in the control of TRA1 expression, linking TORC1 and cell growth regulation to the SAGA acetyltransferase complex during misfolded protein stress.

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“…This inconsistency is partly due to the fact that MYC is able to modulate the transcription of up to 15% of all protein coding genes (8,9). Another layer of complexity is added by the finding that MYC can interact with several proteins able to induce chromatin modifications associated with active transcription, like TRRAP (10), GCN5 (11), and TIP60 (12). MYC was also found bound to components of the P-TEFb complex and to influence general transcriptional pause release (13).…”

Section: Significancementioning

confidence: 99%

MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

Doose¹,

Haake

Bernhart³

et al. 2015

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

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Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long noncoding RNAs (lncRNAs), on MYC ability to influence the cellular transcriptome. Here, we have intersected RNA-sequencing data from two MYC-inducible cell lines and a cohort of 91 B-cell lymphomas with or without genetic variants resulting in MYC overexpression. We identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them, we focused on a lncRNA that we named MYC-induced long noncoding RNA (MINCR), showing a strong correlation with MYC expression in MYC-positive lymphomas. To understand its cellular role, we performed RNAi and found that MINCR knockdown is associated with an impairment in cell cycle progression. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown. Interestingly, these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. Accordingly, MINCR knockdown was associated with a reduction in MYC binding to the promoters of selected cell cycle genes. Finally, we show that down-regulation of Aurora kinases A and B and chromatin licensing and DNA replication factor 1 may explain the reduction in cellular proliferation observed on MINCR knockdown. We, therefore, suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.MYC | lncRNA | cell cycle | B-cell lymphoma M YC is a transcription factor belonging to the basic helixloop-helix zipper family that was originally identified in Burkitt lymphoma (BL) because of a chromosomal translocation that juxtaposes the MYC oncogene with one of three immunoglobulin (Ig) loci (1-3). In BL, the deregulation of the oncogenic transcription factor MYC is considered to be the major driving force in lymphoma development (4, 5). MYC overexpression is not restricted to BL and has been found to be a common feature SignificanceGains of the MYC gene are the most common imbalances in cancer and are associated with poor prognosis, particularly in B-cell lymphoma. Recent advances in DNA sequencing have revealed the existence of thousands of long noncoding RNAs (lncRNAs) with unknown functional relevance. We have here identified a MYC-regulated lncRNA that we named MYC-induced long noncoding RNA (MINCR) that has a strong correlation with MYC expression in cancer. We show that MINCR is functional and controls cell cycle progression by influencing the expression of MYC-regulated cell cycle genes. MINCR is, therefore, a novel player in MYC's transcriptional network, with the potential to open new therapeutic windows in the fight against malignant lymphoma and, possibly, all cancers that rely on MYC expression.

show abstract

MYC interacts with the human STAGA coactivator complex via multivalent contacts with the GCN5 and TRRAP subunits

Cited by 44 publications

References 62 publications

Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming

Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming

Sfp1 links TORC1 and cell growth regulation to the yeast SAGA‐complex component Tra1 in response to polyQ proteotoxicity

MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

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