Aifm2, a NADH Oxidase, Supports Robust Glycolysis and Is Required for Cold- and Diet-Induced Thermogenesis

Nguyen, Hai P.; Yi, Danielle; Lin, Frances; Viscarra, José A.; Tabuchi, Chihiro; Ngo, Katina; Shin, Gawon; Lee, Angus Yiu-Fai; Wang, Yuhui; Sul, Hei Sook

doi:10.1016/j.molcel.2019.12.002

Cited by 96 publications

(80 citation statements)

References 49 publications

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“…Also, Aifm2, Dot1L-BKO mice had much smaller peaks around promoters of UCP1, Cox8b and Elovl3 compared to WT mice (Figure 4, right), consistent with significantly decreased thermogenic gene expression in the Dot1L-BKO mice. Also, we found Dot1L-BKO had decreased expression of mitochondrial genes as well as Aifm2, a recently reported BAT-specific enzyme that converts NADH to NAD to sustain robust glycolysis to fuel thermogenesis (Nguyen et al, 2020). These data suggest that H3K79me2/3 by Dot1L is important for creating a chromatin landscape permissive to transcription in BAT upon cold stimulation.…”

Section: Genome Wide Analysis For Dot1l Effect On Chromatin Accessibisupporting

confidence: 64%

Dot1L interacts with Zc3h10 to activate UCP1 and other thermogenic genes

Yi¹,

Nguyen²,

Dinh³

et al. 2020

Preprint

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13Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical 14 energy into heat, thereby increasing energy expenditure. Here, we identify Dot1L, the only 15 known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally 16 activates the UCP1 promoter and other BAT genes. Through a direct interaction, Dot1L is 17 recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator 18 by methylating H3K79. We also show that Dot1L is induced during brown fat cell differentiation 19 and by cold exposure and that Dot1L and its H3K79 methyltransferase activity is required for 20 thermogenic gene program. Furthermore, we demonstrate that Dot1L ablation in mice using 21 UCP1-Cre prevents activation of UCP1 and other target genes to reduce thermogenic capacity 22 and energy expenditure, promoting adiposity. Hence, Dot1L plays a critical role in the 23 thermogenic program and may present as a future target for obesity therapeutics. 24 25 42 UCP1 gene. A multitude of transcriptional regulators have been implicated in the transcription of 43 UCP1, including transcription factors, Zfp516, IRF4 and EBF2, and transcriptional coregulators,

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Section: Genome Wide Analysis For Dot1l Effect On Chromatin Accessibisupporting

confidence: 64%

Dot1L interacts with Zc3h10 to activate UCP1 and other thermogenic genes

Yi¹,

Nguyen²,

Dinh³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Notably, the downregulated thermogenic genes include Ucp1, Cox8b, Elovl3 and Ppargc1a as well as those related to mitochondrion organization and oxidative phosphorylation such as Nrf1, Cox20, Tomm13, and Immp21 ( Figure 5B, left). Also, we found Dot1l-BKO had decreased expression of Aifm2, a recently reported BAT-specific enzyme that converts NADH to NAD to sustain robust glycolysis to fuel thermogenesis (Nguyen et al, 2020). In addition, regulation of triglyceride and carbohydrate catabolism were compromised by Dot1l ablation.…”

Section: Genome Wide Analysis For Dot1l Effect On Chromatin Accessibimentioning

confidence: 55%

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

Nguyen

Dinh

et al. 2020

eLife

Self Cite

View full text Add to dashboard Cite

Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1l, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the Ucp1 promoter and other BAT genes. Through a direct interaction, Dot1l is recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1l is induced during brown fat cell differentiation and by cold exposure and that Dot1l and its H3K79 methyltransferase activity is required for thermogenic gene program. Furthermore, we demonstrate that Dot1l ablation in mice using Ucp1-Cre prevents activation of Ucp1 and other target genes to reduce thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1l plays a critical role in the thermogenic program and may present as a future target for obesity therapeutics.

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“…AIFM2 plays a key role in promoting cell proliferation, invasion, and migration 30 , 31 . Also, AIFM2 was identified as a NADH oxidase, which regenerates NAD to promote glycolysis for thermogenesis 32 . In human breast 33 , gastric 34 and lung 35 cancer cells, apoptosis is mediated by the upregulation of AIFM2 expression and accumulation of AIFM2 in the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

ATF6 aggravates acinar cell apoptosis and injury by regulating p53/AIFM2 transcription in Severe Acute Pancreatitis

Tan¹,

Cao²,

Zhou³

et al. 2020

Theranostics

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Background: There is no curative therapy for severe acute pancreatitis (SAP) due to poor understanding of its molecular mechanisms. Endoplasmic reticulum (ER) stress is involved in SAP and increased expression of ATF6 has been detected in SAP patients. Here, we aimed to investigate the role of ATF6 in a preclinical SAP mouse model and characterize its regulatory mechanism. Methods: Pancreatic tissues of healthy and SAP patients were collected during surgery. Humanized PRSS1 transgenic mice were treated with caerulein to mimic the SAP development, which was crossed to an ATF6 knockout mouse line, and pancreatic tissues from the resulting pups were screened by proteomics. Adenovirus-mediated delivery to the pancreas of SAP mice was used for shRNA-based knockdown or overexpression. The potential functions and mechanisms of ATF6 were clarified by immunofluorescence, immunoelectron microscopy, Western blotting, qRT-PCR, ChIP-qPCR and luciferase reporter assay. Results: Increased expression of ATF6 was associated with elevated apoptosis, ER and mitochondrial disorder in pancreatic tissues from SAP patients and PRSS1 mice. Knockout of ATF6 in SAP mice attenuated acinar injury, apoptosis and ER disorder. AIFM2, known as a p53 target gene, was identified as a downstream regulatory partner of ATF6, whose expression was increased in SAP. Functionally, AIFM2 could reestablish the pathological disorder in SAP tissues in the absence of ATF6. p53 expression was also increased in SAP mice, which was downregulated by ATF6 knockout. p53 knockout significantly suppressed acinar apoptosis and injury in SAP model. Mechanistically, ATF6 promoted AIFM2 transcription by binding to p53 and AIFM2 promoters. Conclusion: These results reveal that ATF6/p53/AIFM2 pathway plays a critical role in acinar apoptosis during SAP progression, highlighting novel therapeutic target molecules for SAP.

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Aifm2, a NADH Oxidase, Supports Robust Glycolysis and Is Required for Cold- and Diet-Induced Thermogenesis

Cited by 96 publications

References 49 publications

Dot1L interacts with Zc3h10 to activate UCP1 and other thermogenic genes

Dot1L interacts with Zc3h10 to activate UCP1 and other thermogenic genes

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

ATF6 aggravates acinar cell apoptosis and injury by regulating p53/AIFM2 transcription in Severe Acute Pancreatitis

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