DNA demethylase ALKBH1 promotes adipogenic differentiation via regulation of HIF-1 signaling

Liu, Yuting; Chen, Yaqian; Wang, Yuan; Jiang, Shuang; Lin, Weimin; Wu, Yaxu; Li, Qiwen; Guo, Yuchen; Liu, Weiqing; Yuan, Quan

doi:10.1016/j.jbc.2021.101499

Cited by 16 publications

(18 citation statements)

References 75 publications

(121 reference statements)

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“…Adipogenic differentiation medium contains 0.5 μM IBMX,1 μM dexamethasone and 10 μg/mL insulin. For hMSCs and 3T3-L1 cells, adipogenic differentiation lasted for 14 days to form mature adipocytes [ 37 ]. All medium was changed every 2 days thereafter.…”

Section: Methodsmentioning

confidence: 99%

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AFF4 regulates cellular adipogenic differentiation via targeting autophagy

Chen

Liu

et al. 2022

PLoS Genet

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Transcriptional elongation is a universal and critical step during gene expression. The super elongation complex (SEC) regulates the rapid transcriptional induction by mobilizing paused RNA polymerase II (Pol II). Dysregulation of SEC is closely associated with human diseases. However, the physiological role of SEC during development and homeostasis remains largely unexplored. Here we studied the function of SEC in adipogenesis by manipulating an essential scaffold protein AF4/FMR2 family member 4 (AFF4), which assembles and stabilizes SEC. Knockdown of AFF4 in human mesenchymal stem cells (hMSCs) and mouse 3T3-L1 preadipocytes inhibits cellular adipogenic differentiation. Overexpression of AFF4 enhances adipogenesis and ectopic adipose tissue formation. We further generate Fabp4-cre driven adipose-specific Aff4 knockout mice and find that AFF4 deficiency impedes adipocyte development and white fat depot formation. Mechanistically, we discover AFF4 regulates autophagy during adipogenesis. AFF4 directly binds to autophagy-related protein ATG5 and ATG16L1, and promotes their transcription. Depleting ATG5 or ATG16L1 abrogates adipogenesis in AFF4-overepressing cells, while overexpression of ATG5 and ATG16L1 rescues the impaired adipogenesis in Aff4-knockout cells. Collectively, our results unveil the functional importance of AFF4 in regulating autophagy and adipogenic differentiation, which broaden our understanding of the transcriptional regulation of adipogenesis.

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Section: Methodsmentioning

confidence: 99%

“…For overexpression, the lentivirus vectors were obtained from GeneChem (oeAFF4, oeATG5, oeATG16L1). Cells transfected with an empty GV358 vectors (Ubi-MCS-3FLAG-SV40-EGFP-IRES-puromycin) were used as control [ 37 ]. Cells were cultured in 6-well to 30% confluence and transfected with lentivirus at an MOI = 20.…”

Section: Methodsmentioning

confidence: 99%

AFF4 regulates cellular adipogenic differentiation via targeting autophagy

Chen

Liu

et al. 2022

PLoS Genet

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“…The sample was then mixed with sample buffer containing 2% SDS and 1% 2-mercaptoethanol and heated at 95 °C for 5 min. The samples were separated on 10% SDS–polyacrylamide gels and transferred to polyvinylidene fluoride (PVDF) membranes using a semi-dry transfer apparatus (Bio-Rad, CA, USA) 59 . Incubation with rabbit anti-METTL3 (1:2 000; Abcam, Cat No: ab195352), rabbit anti-FZD7 (1:1 000; Abcam, Cat No: ab64636), rabbit anti-α-tubulin (1:2 000; Proteintech, Cat No: 11224-1-AP) at 4 °C was conducted overnight, followed by incubation with a horseradish peroxidase (HRP)-conjugated secondary antibody (1:5 000, Cell Signaling Technology, Cat No:7074).…”

Section: Methodsmentioning

confidence: 99%

METTL3-mediated m6A RNA methylation regulates dorsal lingual epithelium homeostasis

et al. 2022

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The dorsal lingual epithelium, which is composed of taste buds and keratinocytes differentiated from K14+ basal cells, discriminates taste compounds and maintains the epithelial barrier. N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotic cells. How METTL3-mediated m6A modification regulates K14+ basal cell fate during dorsal lingual epithelium formation and regeneration remains unclear. Here we show knockout of Mettl3 in K14+ cells reduced the taste buds and enhanced keratinocytes. Deletion of Mettl3 led to increased basal cell proliferation and decreased cell division in taste buds. Conditional Mettl3 knock-in mice showed little impact on taste buds or keratinization, but displayed increased proliferation of cells around taste buds in a protective manner during post-irradiation recovery. Mechanically, we revealed that the most frequent m6A modifications were enriched in Hippo and Wnt signaling, and specific peaks were observed near the stop codons of Lats1 and FZD7. Our study elucidates that METTL3 is essential for taste bud formation and could promote the quantity recovery of taste bud after radiation.

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“…Another study reported that ALKBH1 promoted adipogenic differentiation and contributed to the accumulation of adipose tissue. The results showed that ALKBH1 decreased the 6 mA levels of HIF-1α and GYS1 and then activated the HIF-1 pathway (Liu et al, 2022).…”

Section: Ma and Human Diseasementioning

confidence: 95%

“…(Hao et al, 2020). The hypoxic stress-induced HIF pathway may play an important role in human diseases (Jain et al, 2018;Guo et al, 2020;Liu et al, 2021b;Liu et al, 2022).…”

Section: Ma and Stressmentioning

confidence: 99%

DNA N6-Methyladenine Modification in Eukaryotic Genome

Zhang

Wang

et al. 2022

Front. Genet.

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DNA methylation is treated as an important epigenetic mark in various biological activities. In the past, a large number of articles focused on 5 mC while lacking attention to N6-methyladenine (6 mA). The presence of 6 mA modification was previously discovered only in prokaryotes. Recently, with the development of detection technologies, 6 mA has been found in several eukaryotes, including protozoans, metazoans, plants, and fungi. The importance of 6 mA in prokaryotes and single-celled eukaryotes has been widely accepted. However, due to the incredibly low density of 6 mA and restrictions on detection technologies, the prevalence of 6 mA and its role in biological processes in eukaryotic organisms are highly debated. In this review, we first summarize the advantages and disadvantages of 6 mA detection methods. Then, we conclude existing reports on the prevalence of 6 mA in eukaryotic organisms. Next, we highlight possible methyltransferases, demethylases, and the recognition proteins of 6 mA. In addition, we summarize the functions of 6 mA in eukaryotes. Last but not least, we summarize our point of view and put forward the problems that need further research.

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DNA demethylase ALKBH1 promotes adipogenic differentiation via regulation of HIF-1 signaling

Cited by 16 publications

References 75 publications

AFF4 regulates cellular adipogenic differentiation via targeting autophagy

AFF4 regulates cellular adipogenic differentiation via targeting autophagy

METTL3-mediated m6A RNA methylation regulates dorsal lingual epithelium homeostasis

DNA N6-Methyladenine Modification in Eukaryotic Genome

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