Protein Arginine Methyltransferase PRMT5 Regulates Fatty Acid Metabolism and Lipid Droplet Biogenesis in White Adipose Tissues

Jia, Zhihao; Feng, Yue; Chen, Xiyue; Narayanan, Narayanan; Qiu, Jiamin; Syed, Sabriya A.; Imbalzano, Anthony N.; Deng, Meng; Yu, Peng; Hu, Chang‐Deng; Kuang, Shihuan

doi:10.1002/advs.202002602

Cited by 28 publications

(26 citation statements)

References 73 publications

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“…Meanwhile, the interaction between LSD1 and snail family transcriptional repressor 2 (SNAIL2, also known as SLUG, an important epigenetic regulator of de novo adipose tissue) mediates the demethylation of H3K9 and stimulates FASN expression and lipogenesis Manuel and Haeusler, 2020). Protein arginine methyltransferase 5 (PRMT5) regulates fat cells by promoting the expression of fatty acid synthase (FASN; lipid synthesis gene) by methylating sterol regulatory element binding transcription factor 1 (SREBP1) (Jia et al, 2020).…”

Section: Histone Modificationsmentioning

confidence: 99%

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

Huo

Zhang

Huang

et al. 2021

Front. Cell Dev. Biol.

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Epigenetic modifications and metabolism are two fundamental biological processes. During tumorigenesis and cancer development both epigenetic and metabolic alterations occur and are often intertwined together. Epigenetic modifications contribute to metabolic reprogramming by modifying the transcriptional regulation of metabolic enzymes, which is crucial for glucose metabolism, lipid metabolism, and amino acid metabolism. Metabolites provide substrates for epigenetic modifications, including histone modification (methylation, acetylation, and phosphorylation), DNA and RNA methylation and non-coding RNAs. Simultaneously, some metabolites can also serve as substrates for nonhistone post-translational modifications that have an impact on the development of tumors. And metabolic enzymes also regulate epigenetic modifications independent of their metabolites. In addition, metabolites produced by gut microbiota influence host metabolism. Understanding the crosstalk among metabolism, epigenetic modifications, and gene expression in cancer may help researchers explore the mechanisms of carcinogenesis and progression to metastasis, thereby provide strategies for the prevention and therapy of cancer. In this review, we summarize the progress in the understanding of the interactions between cancer metabolism and epigenetics.

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Section: Histone Modificationsmentioning

confidence: 99%

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

Huo

Zhang

Huang

et al. 2021

Front. Cell Dev. Biol.

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“…Interestingly, PRMT5 has been reported to play a role in metabolic pathways that perpetuate the pathologies of T2DM. For instance, in white adipose tissue, PRMT5 methylates sterol regulatory element-binding transcription factor 1a (SREBP1a) to enhance triacylglycerol formation [67]. PRMT5 also methylates the transcription elongation factor SPT5 to promote lipid droplet biogenesis [67].…”

Section: Prmt5 In Diabetesmentioning

confidence: 99%

“…For instance, in white adipose tissue, PRMT5 methylates sterol regulatory element-binding transcription factor 1a (SREBP1a) to enhance triacylglycerol formation [67]. PRMT5 also methylates the transcription elongation factor SPT5 to promote lipid droplet biogenesis [67]. A separate study also reported that PRMT5 serves as a coactivator for the expression of adipogenic genes, such as peroxisome proliferator-activated receptor γ2 (PPARγ2), adipocyte protein 2 (aP2), adiponectin, leptin, and resistin [68].…”

Section: Prmt5 In Diabetesmentioning

confidence: 99%

The Structure and Functions of PRMT5 in Human Diseases

Motolani

Martin

Sun

et al. 2021

Life

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Since the discovery of protein arginine methyltransferase 5 (PRMT5) and the resolution of its structure, an increasing number of papers have investigated and delineated the structural and functional role of PRMT5 in diseased conditions. PRMT5 is a type II arginine methyltransferase that catalyzes symmetric dimethylation marks on histones and non-histone proteins. From gene regulation to human development, PRMT5 is involved in many vital biological functions in humans. The role of PRMT5 in various cancers is particularly well-documented, and investigations into the development of better PRMT5 inhibitors to promote tumor regression are ongoing. Notably, emerging studies have demonstrated the pathological contribution of PRMT5 in the progression of inflammatory diseases, such as diabetes, cardiovascular diseases, and neurodegenerative disorders. However, more research in this direction is needed. Herein, we critically review the position of PRMT5 in current literature, including its structure, mechanism of action, regulation, physiological and pathological relevance, and therapeutic strategies.

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“…Available reports have demonstrated the role of PRMT5 in regulating lipid biogenesis. Notably, PRMT5 arbitrates seipin-mediated lipid droplet biogenesis in adipocytes (23). Besides, PRMT5 could enhance lipogenesis in cancer cells by methylating SREBP1a (24).…”

Section: Introductionmentioning

confidence: 99%

PRMT5 epigenetically regulates the E3 ubiquitin ligase ITCH to influence lipid accumulation during mycobacterial infection

Borbora¹,

Rajmani

Balaji³

2021

Preprint

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Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), triggers enhanced accumulation of lipids to generate foamy macrophages (FMs). This process has been often attributed to the surge in the expression of lipid influx genes with a concomitant decrease in those involved in lipid efflux genes. Here, we define an Mtb-orchestrated modulation of the ubiquitination mechanism of lipid accumulation markers to enhance lipid accretion during infection. We find that Mtb infection represses the expression of the E3 ubiquitin ligase, ITCH, resulting in the sustenance of key lipid accrual molecules viz. ADRP and CD36, that are otherwise targeted by ITCH for proteasomal degradation. In line, overexpressing ITCH in Mtb-infected cells was found to suppress Mtb-induced lipid accumulation. Molecular analyses including loss-of-function and ChIP assays demonstrated a role for the concerted action of the transcription factor YY1 and the arginine methyl transferase PRMT5 in restricting the expression of Itch gene by conferring repressive symmetrical H4R3me2 marks on its promoter. Consequently, siRNA-mediated depletion of YY1 or PRMT5 rescued ITCH expression, thereby compromising the levels of Mtb-induced ADRP and CD36 and limiting FM formation during infection. Accumulation of lipids within the host has been implicated as a pro-mycobacterial process that aids in pathogen persistence and dormancy. In our study, perturbation of PRMT5 enzyme activity resulted in compromised lipid levels and reduced mycobacterial survival in primary murine macrophages (ex vivo) and in a therapeutic mouse model of TB infection (in vivo). These findings provide new insights on the role of PRMT5 and YY1 in augmenting mycobacterial pathogenesis. Thus, we posit that our observations could help design novel adjunct therapies and combinatorial drug regimen for effective anti-TB strategies.Author SummaryMycobacterium tuberculosis generates lipid-laden cells (foamy macrophages-FMs) that offer a favorable shelter for its persistence. During infection, we observe a significant reduction in the expression of the E3 ubiquitin ligase, ITCH. This repression allows the sustenance of key lipid accretion molecules (ADRP and CD36), by curbing their proteasomal degradation. Further, we show the repression of ITCH to be dependent on the concerted action of the bifunctional transcription factor, YY1 and the arginine methyl transferase, PRMT5. NOTCH signaling pathway was identified as a master-regulator of YY1 expression. In vitro and in vivo analyses revealed the significance of PRMT5 in regulating FM formation and consequently mycobacterial burden.

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Protein Arginine Methyltransferase PRMT5 Regulates Fatty Acid Metabolism and Lipid Droplet Biogenesis in White Adipose Tissues

Cited by 28 publications

References 73 publications

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

The Structure and Functions of PRMT5 in Human Diseases

PRMT5 epigenetically regulates the E3 ubiquitin ligase ITCH to influence lipid accumulation during mycobacterial infection

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