DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation

Shuai, Lei; Li, Bohan; Jiang, Haowen; Yang, Lin; Li, Jia

doi:10.2337/db20-1110

Cited by 7 publications

(3 citation statements)

References 56 publications

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“…DOT1L, as the sole methyltransferase, assumes the critical responsibility of facilitating the mono- and dimethylation modification of H3K79. This enzymatic activity subsequently exerts a profound influence on the expression of genes associated with crucial biological processes, including cholesterol synthesis pathways[ 50 ], lymphatic system development[ 51 ], and thermogenic adipocyte differentiation[ 52 ].…”

Section: Histone Methylation In Metabolic Homeostasismentioning

confidence: 99%

Unraveling the relationship between histone methylation and nonalcoholic fatty liver disease

Xu,

Fan,

Zhang

et al. 2024

World J Hepatol

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Non-alcoholic fatty liver disease (NAFLD) poses a significant health challenge in modern societies due to shifts in lifestyle and dietary habits. Its complexity stems from genetic predisposition, environmental influences, and metabolic factors. Epigenetic processes govern various cellular functions such as transcription, chromatin structure, and cell division. In NAFLD, these epigenetic tendencies, especially the process of histone methylation, are intricately intertwined with fat accumulation in the liver. Histone methylation is regulated by different enzymes like methyltransferases and demethylases and influences the expression of genes related to adipogenesis. While early-stage NAFLD is reversible, its progression to severe stages becomes almost irreversible. Therefore, early detection and intervention in NAFLD are crucial, and understanding the precise role of histone methylation in the early stages of NAFLD could be vital in halting or potentially reversing the progression of this disease.

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Section: Histone Methylation In Metabolic Homeostasismentioning

confidence: 99%

Unraveling the relationship between histone methylation and nonalcoholic fatty liver disease

Xu,

Fan,

Zhang

et al. 2024

World J Hepatol

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show abstract

“…This is especially interesting on the basis that DOT1L limits inflammation and the fact that proinflammatory cytokines may increase the risk for obesity. Interestingly, DOT1L is a regulator of thermogenic adipocyte differentiation and function, and is thereby a key epigenetic modifier in obesity ( 97 ), showing that DOT1L may pose a highly interesting target (e.g. by stabilising its activity or by providing sufficient substrate) in obesity.…”

Section: Innate Immune Systemmentioning

confidence: 99%

An emerging maestro of immune regulation: how DOT1L orchestrates the harmonies of the immune system

Kealy,

Runting,

Thiele

et al. 2024

Front. Immunol.

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The immune system comprises a complex yet tightly regulated network of cells and molecules that play a critical role in protecting the body from infection and disease. The activity and development of each immune cell is regulated in a myriad of ways including through the cytokine milieu, the availability of key receptors, via tailored intracellular signalling cascades, dedicated transcription factors and even by directly modulating gene accessibility and expression; the latter is more commonly known as epigenetic regulation. In recent years, epigenetic regulators have begun to emerge as key players involved in modulating the immune system. Among these, the lysine methyltransferase DOT1L has gained significant attention for its involvement in orchestrating immune cell formation and function. In this review we provide an overview of the role of DOT1L across the immune system and the implications of this role on health and disease. We begin by elucidating the general mechanisms of DOT1L-mediated histone methylation and its impact on gene expression within immune cells. Subsequently, we provide a detailed and comprehensive overview of recent studies that identify DOT1L as a crucial regulator of immune cell development, differentiation, and activation. Next, we discuss the potential mechanisms of DOT1L-mediated regulation of immune cell function and shed light on how DOT1L might be contributing to immune cell homeostasis and dysfunction. We then provide food for thought by highlighting some of the current obstacles and technical limitations precluding a more in-depth elucidation of DOT1L’s role. Finally, we explore the potential therapeutic implications of targeting DOT1L in the context of immune-related diseases and discuss ongoing research efforts to this end. Overall, this review consolidates the current paradigm regarding DOT1L’s role across the immune network and emphasises its critical role in governing the healthy immune system and its potential as a novel therapeutic target for immune-related diseases. A deeper understanding of DOT1L’s immunomodulatory functions could pave the way for innovative therapeutic approaches which fine-tune the immune response to enhance or restore human health.

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“…Lysine methyltransferase 5C (KMT5C), a H4K20 methyltransferase, positively regulates thermogenesis through regulating the expression of transformation related protein 53 ( Trp53 ), a repressor of thermogenic program ( 69 ). DOT1-like (DOT1L), a lysine 79 of histone H3 (H3K79) methyltransferase, inhibits thermogenic adipocyte differentiation and function through repressing the expression of brown adipocyte tissue-selective genes ( 70 ).…”

Section: Molecular Regulations Of Thermogenesis Of Brown and Beige Ad...mentioning

confidence: 99%

Molecular and cellular regulation of thermogenic fat

Wang

2023

Front. Endocrinol.

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Thermogenic fat, consisting of brown and beige adipocytes, dissipates energy in the form of heat, in contrast to the characteristics of white adipocytes that store energy. Increasing energy expenditure by activating brown adipocytes or inducing beige adipocytes is a potential therapeutic strategy for treating obesity and type 2 diabetes. Thus, a better understanding of the underlying mechanisms of thermogenesis provides novel therapeutic interventions for metabolic diseases. In this review, we summarize the recent advances in the molecular regulation of thermogenesis, focusing on transcription factors, epigenetic regulators, metabolites, and non-coding RNAs. We further discuss the intercellular and inter-organ crosstalk that regulate thermogenesis, considering the heterogeneity and complex tissue microenvironment of thermogenic fat.

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DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation

Cited by 7 publications

References 56 publications

Unraveling the relationship between histone methylation and nonalcoholic fatty liver disease

Unraveling the relationship between histone methylation and nonalcoholic fatty liver disease

An emerging maestro of immune regulation: how DOT1L orchestrates the harmonies of the immune system

Molecular and cellular regulation of thermogenic fat

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