Transcriptional regulation of brown and beige adipocyte differentiation by EBF2

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R-HSA-9844594
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Pathway
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Homo sapiens
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5/5
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Transcriptional regulation of brown and beige adipocyte differentiation by EBF2
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EBF2 (Early B-cell factor 2) is a transcription factor that marks committed brown and beige preadipocytes. EBF2 cooperates with PPARG, a master regulator of adipogenesis, to activate the brown/beige adipocyte thermogenic program (inferred from mouse homologs in Rajakumari et al. 2013). In white adipocytes, the activity of EBF2 is negatively regulated by binding of the transcription factor ZNF423, a key transcription factor for white adipocyte differentiation. In brown/beige fate-committed cells, the interaction between ZNF423 and EBF2 is impeded by BMP7, which acts as a positive regulator of brown/beige adipogenesis (inferred from mouse homologs in Shao et al. 2016; Shao et al. 2021). Direct transcriptional targets of EBF2 include PRDM16, UCP1, and PPARA genes. Other marker genes of brown/beige adipocytes, such as CIDEA, PPARGC1A, COX7A, and DIO2 are positively regulated by EBF2 and probably also direct targets of EBF2 (inferred from mouse homologs in Rajakumari et al. 2013; Wang et al. 2014; Stine et al. 2016; Shapira et al. 2017; Lai et al. 2017; Angueira et al. 2020). Based on mouse studies, EBF1 may function partially redundantly with EBF2 in regulation of thermogenesis genes (Angueira et al. 2020). Transcriptional activity of EBF2 is positively regulated by binding of the long noncoding RNA (lncRNA) Blnc1 (inferred from mouse homologs in Zhao et al. 2014; Mi et al. 2017). Based on mouse studies, EBF2 was reported to recruit the BAF chromatin remodeling complex to activate the transcription of target genes (Shapira et al. 2017; Liu et al. 2020). In addition to PPARG, based on mouse studies, EBF2 was reported to cooperate with other transcription factors such as SIX1 during brown/beige adipogenesis (Brunmeir et al. 2016). Besides ZNF423, based on mouse studies, other transcription factors, such as ID1 (Patil et al. 2017) and TLE3 (Pearson et al. 2019), have been reported to act as inhibitors of EBF2-mediated transcription. The transcription factor GATA6 was reported to directly stimulate EBF2 transcription during mouse beige/brown thermogenesis (Jun et al. 2023). Besides BPM7, BPM9-mediated upregulation of FGFR3 (Yamamoto et al. 2022), and FGF11 (Jiang et al. 2023) have been reported as indirect activators of EBF2 transcriptional activity in mouse and goat, respectively. ZAG (Zinc-alpha2-glycoprotein), a tumor secretory factor, has been reported to stimulate EBF2 expression, which contributes to white adipose tissue browning and energy wasting in cancer-related cachexia (Elattar et al. 2018). In the single cell atlas of human white adipose tissue (Emont et al. 2022) it was reported that the EBF2-positive hAd6 white adipocyte subpopulation with UCP1 expression, consistent with the beige profile, shows an association with increased BMI and visceral adiposity. For review, please refer to Wang and Seale 2016.
Literature References
PubMed ID Title Journal Year
34620682 ZFP423 controls EBF2 coactivator recruitment and PPARγ occupancy to determine the thermogenic plasticity of adipocytes

Shan, B, Shao, M, Seale, P, Vishvanath, L, Zhang, Q, Li, L, Gupta, RK, Truong, A

Genes Dev 2021
25002143 A long noncoding RNA transcriptional regulatory circuit drives thermogenic adipocyte differentiation

Yu, Q, Zhao, XY, Wang, GX, Li, S, Lin, JD

Mol Cell 2014
27552974 Control of brown and beige fat development

Wang, W, Seale, P

Nat Rev Mol Cell Biol 2016
37647897 Control of murine brown adipocyte development by GATA6

Fein, EC, Sakers, AP, Angueira, AR, Seale, P, Jun, S, Weller, AH, Tan, JME, Stine, RR, Batmanov, K, Cheng, L, Ishibashi, J

Dev Cell 2023
32130892 Early B Cell Factor Activity Controls Developmental and Adaptive Thermogenic Gene Programming in Adipocytes

Titchenell, PM, Angueira, AR, Seale, P, Lim, HW, Sostre-Colón, J, Sampat, S, Shapira, SN, Lazar, MA, Emmett, MJ, Ishibashi, J

Cell Rep 2020
32404872 BAF60a deficiency uncouples chromatin accessibility and cold sensitivity from white fat browning

Liu, T, Parker, SCJ, Orchard, P, Zhao, XY, Yu, Q, Li, S, Mi, L, Xiong, J, Yu, L, Lin, JD, Meng, ZX

Nat Commun 2020
28398509 MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis

Ge, K, Wang, L, Jang, Y, Lee, JE, Lai, B, Peng, W

Nucleic Acids Res 2017
28428261 EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex

Rajakumari, S, Harms, MJ, Sakers, AP, Seale, P, Lim, HW, Won, KJ, Shapira, SN, Ishibashi, J

Genes Dev 2017
31123067 Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism

Lee, S, Simcox, J, Rajbhandari, P, Mandrup, S, Loft, A, Villanueva, CJ, Pearson, S, Tontonoz, P

Genes Dev 2019
35738051 Factors affecting the induction of uncoupling protein 1 in C2C12 myogenic cells

Murakami, M, Funaba, M, Shimokawa, F, Yamamoto, T, Matsui, T, Diao, Z

Cytokine 2022
25197048 Ebf2 is a selective marker of brown and beige adipogenic precursor cells

Rajakumari, S, Kissig, M, Wang, W, Seale, P, Lim, HW, Won, KJ, Huang, L

Proc Natl Acad Sci U S A 2014
23499423 EBF2 determines and maintains brown adipocyte identity

Rajakumari, S, Seale, P, Lim, HW, Wu, J, Won, KJ, Reed, RR, Giang, AH, Ishibashi, J

Cell Metab 2013
27238639 Zfp423 Maintains White Adipocyte Identity through Suppression of the Beige Cell Thermogenic Gene Program

MacPherson, KA, Kusminski, CM, Shao, M, Seale, P, Vishvanath, L, Holland, WL, Sun, K, Hepler, C, Wang, QA, Gupta, RK, Spurgin, SB, Ishibashi, J

Cell Metab 2016
26844207 EBF2 promotes the recruitment of beige adipocytes in white adipose tissue

Harms, M, Seale, P, Lim, HW, Won, KJ, Shapira, SN, Stine, RR, Ishibashi, J

Mol Metab 2016
35296864 A single-cell atlas of human and mouse white adipose tissue

Dashti, H, Tobias, A, Kramer, Z, Pant, D, Gulko, A, Veregge, ML, Boyd, CG, Strobel, S, Ducie, J, Jacobs, C, Merkel, E, Ashenberg, O, Tsai, LT, Laber, S, Colleluori, G, Regev, A, McGonagle, E, Kar, A, Srinivasan, H, Jørgensen, AM, Tenen, D, Khera, AV, Emont, MP, Di Vincenzo, A, Gourash, W, Claussnitzer, M, Essene, AL, Lee, BT, Rosen, ED, Agrawal, S, Courcoulas, A, Morris, D, Lin, SJ, De Filippis, E, Stefek, A, Westcott, GP, Pers, TH, Giordano, A

Nature 2022
28270523 Id1 Promotes Obesity by Suppressing Brown Adipose Thermogenesis and White Adipose Browning

Kapil, S, Yuan, J, Satyanarayana, A, Patil, M, Elattar, S, Chang, J, Sharma, BK

Diabetes 2017
28123941 Conserved function of the long noncoding RNA Blnc1 in brown adipocyte differentiation

Zhao, XY, Li, S, Mi, L, Yang, G, Lin, JD

Mol Metab 2017
29570397 The tumor secretory factor ZAG promotes white adipose tissue browning and energy wasting

Dimri, M, Satyanarayana, A, Elattar, S

FASEB J 2018
27923061 Comparative Transcriptomic and Epigenomic Analyses Reveal New Regulators of Murine Brown Adipogenesis

Xu, F, Julien, SG, Xie, W, Wu, J, Kim, SY, Peng, X, Zhang, Q, Brunmeir, R

PLoS Genet 2016
37446019 Transcriptomic Analysis Reveals Fibroblast Growth Factor 11 (FGF11) Role in Brown Adipocytes in Thermogenic Regulation of Goats

Liu, X, Su, D, Wang, L, Wang, Y, Jiang, T

Int J Mol Sci 2023
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Authored
Orlic-Milacic, M  (2023-09-25)
Reviewed
Chun, TH  (2023-11-29)
Created
Orlic-Milacic, M  (2023-09-21)
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