The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation

Aylon, Yael; Gershoni, Anat; Rotkopf, Ron; Biton, Inbal E.; Porat, Ziv; Koh, Anna P.; Sun, Xiaochen; Lee, Young-Min; Fiel, M. Isabel; Hoshida, Yujin; Friedman, Scott L.; Johnson, Randy L.; Oren, Moshe

doi:10.1101/gad.274167.115

Cited by 84 publications

(73 citation statements)

References 53 publications

(57 reference statements)

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“…Accordingly, the regulation of DNMT and TET genes may ultimately determine the dynamics of DNA methylation in pluripotent states. p53 is a pivotal tumor suppressor, playing major roles in maintaining genome stability (Levine and Oren 2009;Qiu et al 2011;Carvajal and Manfredi 2013;Aylon et al 2016). Functional p53 is linked to maintenance of the epigenome (Levine and Greenbaum 2012) and specifically DNA methylation of retroelements (Leonova et al 2013).…”

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confidence: 99%

p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity

et al. 2017

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DNA methylation is a key regulator of embryonic stem cell (ESC) biology, dynamically changing between naïve, primed, and differentiated states. The p53 tumor suppressor is a pivotal guardian of genomic stability, but its contributions to epigenetic regulation and stem cell biology are less explored. We report that, in naïve mouse ESCs (mESCs), p53 restricts the expression of the de novo DNA methyltransferases Dnmt3a and Dnmt3b while upregulating Tet1 and Tet2, which promote DNA demethylation. The DNA methylation imbalance in p53-deficient (p53 −/− ) mESCs is the result of augmented overall DNA methylation as well as increased methylation landscape heterogeneity. In differentiating p53−/− mESCs, elevated methylation persists, albeit more mildly. Importantly, concomitant with DNA methylation heterogeneity, p53−/− mESCs display increased cellular heterogeneity both in the "naïve" state and upon induced differentiation. This impact of p53 loss on 5-methylcytosine (5mC) heterogeneity was also evident in human ESCs and mouse embryos in vivo. Hence, p53 helps maintain DNA methylation homeostasis and clonal homogeneity, a function that may contribute to its tumor suppressor activity.[Keywords: DNA methylation; p53; stem cells] Supplemental material is available for this article. DNA methylation is a key epigenetic mark that is correlated with the major transitions during embryogenesis and other developmental processes. Differentiation and dedifferentiation of mouse embryonic stem cells (mESCs) provide a model for analyzing the regulation and possible functional roles of DNA methylation in maintaining pluripotency and facilitating differentiation. For example, when mESCs are induced to undergo differentiation, the transcriptional network ensuring pluripotency is silenced, and de novo DNA methylation is observed at promoters of key pluripotency factors (Thiagarajan et al. 2014). Conversely, when serum-maintained mESCs are moved to serum-free conditions with two kinase inhibitors (2i), their developmental potential is enhanced alongside substantial loss of DNA methylation . These transitions recapitulate early embryonic stages (Nichols and Smith 2009;Martin Gonzalez et al. 2016), but the mechanisms modulating DNA methylation remain to be fully characterized. The DNA methylation machinery is crucial for lineage specification, and mice lacking functional DNA methyltransferases (DNMTs) fail to develop properly (Siegfried and Cedar 1997;Smith and Meissner 2013); therefore, more comprehensive elucidation of the regulation of DNA methylation is pivotal to understanding the pluripotent state.In mammals, DNA methylation is governed by three DNMTs: Dnmt3a and Dnmt3b, responsible for setting de novo DNA methylation patterns, and Dnmt1, required primarily for maintenance of such patterns. In addition, TET enzymes (Tet1 and Tet2 in mESCs) facilitate demethylation by catalyzing oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which, by sequential oxidation steps, provides the substrate for reversal to unmethylated...

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p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity

et al. 2017

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“…35 Mice harbouring liver-specific Lats2 conditional knockout displayed SREBP activation, leading to spontaneous fatty liver disease. 35 Mice harbouring liver-specific Lats2 conditional knockout displayed SREBP activation, leading to spontaneous fatty liver disease.…”

Section: Discussionmentioning

confidence: 99%

A functional interaction between Hippo‐YAP signalling and SREBPs mediates hepatic steatosis in diabetic mice

Shu

Gao

Zhang

et al. 2019

J Cellular Molecular Medi

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The Hippo pathway is an evolutionarily conserved regulator of organ size and tumorigenesis that negatively regulates cell growth and survival. Whether the Hippo pathway regulates cell metabolism is unknown. Here, we report that in the nucleus of hepatocytes, Yes‐associated protein(YAP)—the terminal effector of the Hippo pathway—directly interacts with sterol regulatory element binding proteins (SREBP‐1c and SREBP‐2) on the promoters of the fatty acid synthase (FAS) and 30‐hydroxylmethyl glutaryl coenzyme A reductase (HMGCR), thereby stimulating their transcription and promoting hepatocyte lipogenesis and cholesterol synthesis. In diet‐induced diabetic mice, either Lats1 overexpression or YAP knockdown protects against hepatic steatosis and hyperlipidaemia through suppression of the interaction between YAP and SREBP‐1c/SREBP‐2. These results suggest that YAP is a nuclear co‐factor of SREBPs and that the Hippo pathway negatively affects hepatocyte lipogenesis by inhibiting the function of YAP‐SREBP complexes.

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“…Mice that have a liver-specific disruption of Lats2 have increased expression of SREBP target genes, resulting in increased cholesterol synthesis and the development of steatosis 90 . This phenotype occurs independently of YAP, indicating that the Hippo pathway can regulate metabolic homeostasis through multiple effectors.…”

Section: Emerging Roles In Liver Zonationmentioning

confidence: 99%

Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis

2017

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The Hippo signaling pathway, also known as the Salvador–Warts–Hippo pathway, is a regulator of organ size. The pathway takes its name from the Drosophila protein kinase, Hippo (STK4/MST1 and STK3/MST2 in mammals), which, when inactivated, leads to considerable tissue overgrowth. In mammals, MST1 and MST2 negatively regulate the transcriptional co-activators yes-associated protein 1 (YAP) and WW domain containing transcription regulator 1 (WWTR1/TAZ), which together regulate the expression of genes that control proliferation, survival, and differentiation. YAP and TAZ activation have been associated with liver development, regeneration, and tumorigenesis. How their activity is dynamically regulated in these contexts, however, is just beginning to be elucidated. We review the mechanisms of Hippo signaling in the liver and explore outstanding questions for future research.

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The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation

Cited by 84 publications

References 53 publications

p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity

p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity

A functional interaction between Hippo‐YAP signalling and SREBPs mediates hepatic steatosis in diabetic mice

Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis

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