Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

Yi, Danielle; Nguyen, Hai P.; Dinh, Jennie; Viscarra, José A.; Xie, Ying; Lin, Frances; Zhu, Madeleine; Dempersmier, Jon; Wang, Yuhui; Sul, Hei Sook

doi:10.7554/elife.59990

Cited by 12 publications

(12 citation statements)

References 46 publications

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“…The seeming contradiction between downregulated thermogenic gene expression suggested by Yi et al (37) and our observations on DOT1L-deficient BAT cells can be explained by the distinct time point of DOT1L loss and effects on differentiation. To further demonstrate it, we established two methods to knockdown Dot1L by transfecting with siRNA targeting Dot1L at day À3 before initiation of differentiation or at day 2 of differentiation, and then we examined lipid accumulation and gene expression in differentiated brown adipocytes.…”

Section: Deletion Of Dot1l In Preadipocytes Promotes Brown and Beige ...contrasting

confidence: 99%

“…To further demonstrate it, we established two methods to knockdown Dot1L by transfecting with siRNA targeting Dot1L at day À3 before initiation of differentiation or at day 2 of differentiation, and then we examined lipid accumulation and gene expression in differentiated brown adipocytes. Consistent with results in the article by Yi et al (37), knockdown of DOT1L did not affect brown adipogenesis when siRNA was transfected at day 2 of differentiation, whereas knockdown of DOT1L significantly increased brown adipocyte differentiation when siRNA was transfected before initiation of differentiation (Supplementary Fig. 10D and E).…”

Section: Deletion Of Dot1l In Preadipocytes Promotes Brown and Beige ...supporting

confidence: 90%

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DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation

Shuai

Jiang

et al. 2021

Diabetes

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Brown and beige adipocytes are characterized as thermogenic adipocytes and have great potential for treating obesity and associated metabolic diseases. In this article, we identify a conserved mammalian lysine 79 of histone H3 (H3K79) methyltransferase, disruptor of telomeric silencing-1 like (DOT1L), as a new epigenetic regulator that controls thermogenic adipocyte differentiation and function. We show that deletion of DOT1L in thermogenic adipocytes potently protects mice from diet-induced obesity, improves glucose homeostasis, alleviates hepatic steatosis, and facilitates adaptive thermogenesis in vivo. Loss of DOT1L in primary preadipocytes significantly promotes brown and beige adipogenesis and thermogenesis in vitro. Mechanistically, DOT1L epigenetically regulates the brown adipose tissue–selective gene program by modulating H3K79 methylation, in particular H3K79me2 modification. Thus, our study demonstrates that DOT1L exerts an important role in energy homeostasis by regulating thermogenic adipocyte differentiation and function.

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Section: Deletion Of Dot1l In Preadipocytes Promotes Brown and Beige ...contrasting

confidence: 99%

Section: Deletion Of Dot1l In Preadipocytes Promotes Brown and Beige ...supporting

confidence: 90%

DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation

Shuai

Jiang

et al. 2021

Diabetes

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“…An additional mechanism of fine-tuning of DOT1L activity is achieved by its cofactor-mediated recruitment to specific genomic locations. The known examples of this type of regulation are the transcription factor-mediated DOT1L recruitment to promoter regions of target genes ( Cho et al, 2015 ; Nassa et al, 2019 ; Yi et al, 2020 ) and the stimulation of its activity by binding to mono-ubiquitinated histone H2B ( Valencia-Sánchez et al, 2019 ; Spangler et al, 2022 ) and histone H4 tail that result in the precise positioning of the methyltransferase catalytic center above H3K79 ( Worden et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

et al. 2022

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The histone lysine methyltransferase DOT1L (DOT1-like histone lysine methyltransferase) is responsible for the epigenetic regulation of gene expression through specific methylation of lysine79 residue of histone H3 (H3K79) in actively transcribed genes. Its normal activity is crucial for embryonic development and adult tissues functions, whereas its aberrant functioning is known to contribute to leukemogenesis. DOT1L is the only lysine methyltransferase that does not contain a SET domain, which is a feature that allowed the development of selective DOT1L inhibitors that are currently investigated in Phase I clinical trials for cancer treatment. Recently, abnormal expression of this enzyme has been associated with poor survival and increased aggressiveness of several solid tumors. In this review evidences of aberrant DOT1L expression and activity in breast, ovarian, prostate, colon, and other solid tumors, and its relationships with biological and clinical behavior of the disease and response to therapies, are summarized. Current knowledge of the structural basis of DOT1L ability to regulate cell proliferation, invasion, plasticity and stemness, cell cycle progression, cell-to-cell signaling, epithelial-to-mesenchymal transition, and chemoresistance, through cooperation with several molecular partners including noncoding RNAs, is also reviewed. Finally, available options for the treatment of therapeutically challenging solid tumors by targeting DOT1L are discussed.

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“…Coincidentally, Zhou et al (60) also reported SAMD4A as a novel breast tumour angiogenesis suppressor in breast cancer. ZC3H10 regulates lipid metabolism and may also offer novel routes toward treatments for obesity (61).…”

Section: Discussionmentioning

confidence: 99%

Identification of Circular RNA-Based Immunomodulatory Networks in Colorectal Cancer

Feng

et al. 2022

Front. Oncol.

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BackgroundCircular RNAs (circRNAs) have been recently proposed as hub molecules in various diseases, especially in tumours. We found that circRNAs derived from ribonuclease P RNA component H1 (RPPH1) were highly expressed in colorectal cancer (CRC) samples from Gene Expression Omnibus (GEO) datasets.ObjectiveWe sought to identify new circRNAs derived from RPPH1 and investigate their regulation of the competing endogenous RNA (ceRNA) and RNA binding protein (RBP) networks of CRC immune infiltration.MethodsThe circRNA expression profiles miRNA and mRNA data were extracted from the GEO and The Cancer Genome Atlas (TCGA) datasets, respectively. The differentially expressed (DE) RNAs were identified using R software and online server tools, and the circRNA–miRNA–mRNA and circRNA–protein networks were constructed using Cytoscape. The relationship between targeted genes and immune infiltration was identified using the GEPIA2 and TIMER2 online server tools.ResultsA ceRNA network, including eight circRNAs, five miRNAs, and six mRNAs, was revealed. Moreover, a circRNA–protein network, including eight circRNAs and 49 proteins, was established. The targeted genes, ENOX1, NCAM1, SAMD4A, and ZC3H10, are closely related to CRC tumour-infiltrating macrophages.ConclusionsWe analysed the characteristics of circRNA from RPPH1 as competing for endogenous RNA binding miRNA or protein in CRC macrophage infiltration. The results point towards the development of a new diagnostic and therapeutic paradigm for CRC.

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Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

Cited by 12 publications

References 46 publications

DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation

DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation

Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

Identification of Circular RNA-Based Immunomodulatory Networks in Colorectal Cancer

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