Kinetic profiling of the c-Myc transcriptome and bioinformatic analysis of repressed gene promoters

Yap, Chui-Sun; Peterson, Adam; Castellani, Gastone; Sedivy, John M.; Neretti, Nicola

doi:10.4161/cc.10.13.16249

Cited by 40 publications

(43 citation statements)

References 67 publications

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“…Independent of the anti-proliferative effects of MYC and G9a, we show that depleting G9a protein or inhibiting its catalytic activity preferentially hinders MYC binding at repressed genes and shifts repressed loci marked by H3K9me2 to active epigenetic states, leading to upregulated gene expression. Although E-box motifs have been reported to strongly associate with MYC-activated genes (Yap et al, 2011), our genome-wide data show that (C) mRNA expression of MYC-activated and -repressed genes in MDAMB231 and SKBR3 treated with UNC0642 or DMSO control for 96 hr (n = 3; mean ± SD; Bonferroni corrected one-way ANOVA compared with DMSO). (D) ChIP-qPCR for H3K9me2, MYC, or IgG in MDAMB231 and SKBR3 treated with 2 mM UNC0642 or DMSO (n = 3 for MDAMB231, n = 4 for SKBR3; mean ± SD; Bonferroni corrected two-way ANOVA compared with DMSO).…”

Section: Discussionmentioning

confidence: 88%

MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis

et al. 2018

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Graphical Abstract Highlights d MYC interacts with and regulates the G9a histone methyltransferase complex d G9a is required for MYC chromatin binding and gene repression d MYC-G9a interaction requires the transformation-dependent MYC box II region d G9a is a synthetic lethal vulnerability in MYC-dependent basal breast cancer SUMMARYMYC is an oncogenic driver that regulates transcriptional activation and repression. Surprisingly, mechanisms by which MYC promotes malignant transformation remain unclear. We demonstrate that MYC interacts with the G9a H3K9-methyltransferase complex to control transcriptional repression. Inhibiting G9a hinders MYC chromatin binding at MYC-repressed genes and de-represses gene expression. By identifying the MYC box II region as essential for MYC-G9a interaction, a long-standing missing link between MYC transformation and gene repression is unveiled. Across breast cancer cell lines, the anti-proliferative response to G9a pharmacological inhibition correlates with MYC sensitivity and gene signatures. Consistently, genetically depleting G9a in vivo suppresses MYC-dependent tumor growth. These findings unveil G9a as an epigenetic regulator of MYC transcriptional repression and a therapeutic vulnerability in MYC-driven cancers.

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Section: Discussionmentioning

confidence: 88%

MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis

et al. 2018

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“…Different letters indicate statistical significant differences (P < 0.05). 50 Thus, it is not surprising that cyclins D1 to D3 and cyclins E1 to E2 are among those genes described as "Myc target genes." In the present investigation, we show that RSV suppresses FSH-stimulated Sertoli cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Effect of resveratrol on Sertoli cell proliferation

Gorga

Rindone

Regueira

et al. 2018

J of Cellular Biochemistry

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Resveratrol (RSV), a polyphenolic compound largely found in red grape skin, has been used as a nutritional supplement as it exhibits beneficial health effects, such as anticancer, cardioprotective, antiaging, and anti-inflammatory. Particularly, it has been shown that it participates in the mechanisms involved in cell proliferation. Sirtuin 1 (SIRT1) is considered a well-known RSV effector. Noteworthy, Sirt1-knockout animals are infertile. The aim of this study was, first, to determine whether RSV has any effect on Sertoli cell proliferation and, second, whether SIRT1, a putative target of RSV, is present in immature Sertoli cells. Sertoli cell cultures obtained from 8-day-old rats, which actively proliferate, were treated with RSV (10 and 50 µM) under basal and follicle-stimulating hormone (FSH)-stimulated conditions. Bromodeoxyuridine (BrdU) incorporation and the expression of cyclins D1, D2, D3, E1, and E2 and the Cip/Kip cell cycle inhibitors p21 and p27 were analyzed. RSV decreased BrdU incorporation and cyclins D1, D2, E1, and E2 expression and increased p21 and p27 messenger RNA (mRNA) levels. RSV also decreased FSH-stimulated BrdU incorporation and cyclins D1 and D2 mRNA levels. The effect of RSV on cMYC was also analyzed. RSV treatment did not modify basal and FSH-stimulated cMyc expression; however, it inhibited basal and FSH-stimulated cMYC transcriptional activity, suggesting a role of cMYC in RSV effects. Additionally, Sirt1 was detected in immature Sertoli cells. Altogether, these results suggest that RSV possibly, by activating SIRT1 and regulating cMYC transcriptional activity, participates in the regulation of immature Sertoli cell proliferation.

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“…While in many of the early studies rather late time points were chosen after the activation of MYC and thus it was not clear whether all the regulated genes were indeed direct MYC targets, more recent investigations used also short induction times. In one study several hundred genes were either activated or repressed within 2 and 3 h of MYC activation (Yap et al, 2011). Because in all these analyses RNA levels are measured, effects on RNA processing, in particular RNA stability, may also contribute to the observed differences.…”

Section: Posttranslational Regulation Of Mycmentioning

confidence: 98%