S6K1 Phosphorylation of H2B Mediates EZH2 Trimethylation of H3: A Determinant of Early Adipogenesis

Yi, Sang Ah; Um, Sung Hee; Lee, Jaecheol; Yoo, Jae Ho; Bang, So Young; Park, Eun Kyung; Lee, Min Gyu; Nam, Ki Hong; Jeon, Yeong Jeong; Park, Jong Woo; You, Jueng Soo; Lee, Sang-Jin; Bae, Gyu‐Un; Rhie, Jong Won; Kozma, Sara C.; Thomas, George; Han, Jeung‐Whan

doi:10.1016/j.molcel.2016.03.011

Cited by 72 publications

(78 citation statements)

References 40 publications

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“…Consistently, the phosphorylation of S6, which is a downstream substrate of S6K1, was also higher in the βTC6 cells ( Figure 1D). In line with our previous work, 15 the global level of suppressing histone mark H3K27me3 was parallel to the level of active S6K1, while the active histone mark H3K4me3 showed the opposite tendency ( Figure 1D). As shown in Figure 1, S6K1 exhibited increased activation in β cells, and impaired S6K1 signaling was associated with an increase in the genetic identity of α cells.…”

Section: Involvement Of S6k1 In Pancreatic α/β Cell Identitysupporting

confidence: 92%

S6K1 controls epigenetic plasticity for the expression of pancreatic α/β cell marker genes

Lee

Park

et al. 2018

J of Cellular Biochemistry

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The failure of insulin production by pancreatic β cells is a common hallmark of type 1 diabetes mellitus (T1DM). Because administration of exogenous insulin is associated with diabetes-derived complications, endogenous α to β cell transition can be an attractive alternative. Although decreased β cell size and hypoinsulinaemia have been observed in S6K1-deficient mice, the molecular mechanism underlying the involvement of S6K1 in the transcriptional regulation of insulin remains elusive. Here, we show that the hypoinsulinaemic phenotype of S6K1-deficient mice stems from the dysregulated transcription of a set of genes required for insulin and glucagon production. First, we observed that increased expression of α cell marker genes and decreased expression of β cell marker genes in pancreas tissues from S6K1-deficient mice. Furthermore, S6K1 was highly activated in murine β cell line, βTC6, compared to murine α cell line αTC1. In both α and β cells, active S6K1 promoted the transcription of β cell marker genes, including insulin, whereas S6K1 inhibition increased the transcription of α cell marker genes. Moreover, S6K1 mediated pancreatic gene regulation by modifying two histone marks (activating H3K4me3 and repressing H3K27me3) on gene promoters. These results suggest that S6K1 drives the α to β transition through the epigenetic regulation of cell-specific genes, including insulin and glucagon. This novel role of S6K1 in islet cells provides basic clues to establish therapeutic strategies against T1DM.

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Section: Involvement Of S6k1 In Pancreatic α/β Cell Identitysupporting

confidence: 92%

S6K1 controls epigenetic plasticity for the expression of pancreatic α/β cell marker genes

Lee

Park

et al. 2018

J of Cellular Biochemistry

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“…Inhibition of mTORC1 by either rapamycin treatment or an adipose-specific knockout of regulatory-associated protein of mTOR (also known as RPTOR or raptor, a major component of mTORC1), inhibits adipogenesis1114. Conversely, activation of mTORC1 enhances adipogenesis by increasing PPARγ13, confirming a positive role for mTOR in adipogenesis15. Despite this, mTOR also maintains homeostasis of adipogenesis by suppressing the expression of PPARγ through insulin receptor substrate-1 (IRS-1)/Akt signaling1617, suggesting an indispensable function for mTOR in adipogenesis.…”

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confidence: 95%

PLD1 regulates adipogenic differentiation through mTOR - IRS-1 phosphorylation at serine 636/639

Song

Yoon

2016

Sci Rep

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Phospholipase D1 (PLD1) plays a known role in several differentiation processes, but its role in adipogenic differentiation remains unknown. In the present study, we identified PLD1 as a negative regulator of adipogenic differentiation. We showed that PLD activity was downregulated by both 3-Isobutyl-1-methylxanthine (IBMX) and insulin upon induction of differentiation in 3T3-L1 adipogenic cells. In line with this observation, PLD activity decreased in both high fat diet (HFD)-fed mice and ob/ob mice. We also found that differentiation of 3T3-L1 preadipocytes was enhanced by the depletion of PLD1 levels or inhibition of PLD1 activity by VU0155069, a PLD1-specific inhibitor. Conversely, treatment with phosphatidic acid (PA), a PLD product, and overexpression of PLD1 both caused a decrease in adipogenic differentiation. Moreover, the elevated differentiation in PLD1-knockdown 3T3-L1 cells was reduced by either PA treatment or PLD1 expression, confirming negative roles of PLD1 and PA in adipogenic differentiation. Further investigation revealed that PA displaces DEP domain-containing mTOR-interacting protein (DEPTOR) from mTORC1, which subsequently phosphorylates insulin receptor substrate-1 (IRS-1) at serine 636/639 in 3T3-L1 cells. Taken together, our findings provide convincing evidence for a direct role of PLD1 in adipogenic differentiation by regulating IRS-1 phosphorylation at serine 636/639 through DEPTOR displacement and mTOR activation.

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“…This phosphorylation mark directly promotes the transcription of response genes needed to handle metabolic stress. Other papers report the direct phosphorylation of Ser 36 on H2B by S6K1 (40), which is also a player in the LKB1-AMPK-mTORC1 signaling axis, with S6K1 being phosphorylated by mTORC1. mTORC1 is another player in the epigenetic response to nutrient sensing.…”

Section: Heritable Epigenetic Modifications Acquired Through Microenvmentioning

confidence: 99%

“…Epigenetic marks induced by nutrient sensing proteins and complexes have the ability to greatly alter cellular metabolism, making a useful feed-forward mechanism for acclimation and adaptation to the current metabolic microenvironment. The phosphorylation of Ser 36 on Histone 2B is a significant epigenetic mark made by two proteins involved in nutrient sensing: AMPK and S6K1 (39,40). It has been shown that phosphorylation of Ser 36 on Histone 2B is significantly increased upon treatment of cells with 2-Deoxy Glucose (39), which mimics a glucose deprived environment.…”

Section: Effect Of Heritable Epigenetic Modifications On Tumor Metabomentioning

confidence: 99%

“…It has been shown that phosphorylation of Ser 36 on Histone 2B is significantly increased upon treatment of cells with 2-Deoxy Glucose (39), which mimics a glucose deprived environment. The resulting effect on the cellular transcription from phosphorylation of Ser 36 on Histone 2B by AMPK is the recruitment of EZH2 (40). EZH2 is a histone methyltransferase that trimethylates Lysine 27 on histone 3 when recruited.…”

Section: Effect Of Heritable Epigenetic Modifications On Tumor Metabomentioning

confidence: 99%

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Causes and Consequences of Variable Tumor Cell Metabolism on Heritable Modifications and Tumor Evolution

et al. 2020

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When cancer research advanced into the post-genomic era, it was widely anticipated that the sought-after cure will be delivered promptly. Instead, it became apparent that an understanding of cancer genomics, alone, is unable to translate the wealth of information into successful cures. While gene sequencing has significantly improved our understanding of the natural history of cancer and identified candidates for therapeutic targets, it cannot predict the impact of the biological response to therapies. Hence, patients with a common mutational profile may respond differently to the same therapy, due in part to different microenvironments impacting on gene regulation. This complexity arises from a feedback circuit involving epigenetic modifications made to genes by the metabolic byproducts of cancer cells. New insights into epigenetic mechanisms, activated early in the process of carcinogenesis, have been able to describe phenotypes which cannot be inferred from mutational analyses per se. Epigenetic changes can propagate throughout a tumor via heritable modifications that have long-lasting consequences on ensuing phenotypes. Such heritable epigenetic changes can be evoked profoundly by cancer cell metabolites, which then exercise a broad remit of actions across all stages of carcinogenesis, culminating with a meaningful impact on the tumor's response to therapy. This review outlines some of the cross-talk between heritable epigenetic changes and tumor cell metabolism, and the consequences of such changes on tumor progression.

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S6K1 Phosphorylation of H2B Mediates EZH2 Trimethylation of H3: A Determinant of Early Adipogenesis

Cited by 72 publications

References 40 publications

S6K1 controls epigenetic plasticity for the expression of pancreatic α/β cell marker genes

S6K1 controls epigenetic plasticity for the expression of pancreatic α/β cell marker genes

PLD1 regulates adipogenic differentiation through mTOR - IRS-1 phosphorylation at serine 636/639

Causes and Consequences of Variable Tumor Cell Metabolism on Heritable Modifications and Tumor Evolution

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