The histone methyltransferase SUV420H2 regulates brown and beige adipocyte thermogenesis
Xin Cui, Qiang Cao, Fenfen Li, Jia Jing, Zhixue Liu, Xiaosong Yang, Gary J. Schwartz, Liqing Yu, Huidong Shi, Hang Shi, Bingzhong Xue
Xin Cui, Qiang Cao, Fenfen Li, Jia Jing, Zhixue Liu, Xiaosong Yang, Gary J. Schwartz, Liqing Yu, Huidong Shi, Hang Shi, Bingzhong Xue
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Research Article Metabolism

The histone methyltransferase SUV420H2 regulates brown and beige adipocyte thermogenesis

Abstract

Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Here we discover that histone methyltransferase suppressor of variegation 4–20 homolog 2 (Suv420h2) expression parallels that of Ucp1 in brown and beige adipocytes and that Suv420h2 knockdown significantly reduces — whereas Suv420h2 overexpression significantly increases — Ucp1 levels in brown adipocytes. Suv420h2 knockout (H2KO) mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study shows that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4e-bp1) promoter, leading to downregulated expression of 4e-bp1, a negative regulator of the translation initiation complex. This in turn upregulates PGC1α protein levels, and this upregulation is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.

Authors

Xin Cui, Qiang Cao, Fenfen Li, Jia Jing, Zhixue Liu, Xiaosong Yang, Gary J. Schwartz, Liqing Yu, Huidong Shi, Hang Shi, Bingzhong Xue

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Figure 1

Suv420h2 regulates Ucp1 expression.

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Suv420h2 regulates Ucp1 expression. (A and B) Ucp1 (A) and Suv420h2 (B)...
(A and B) Ucp1 (A) and Suv420h2 (B) expression in iWAT of male C57BL/6J mice during postnatal development, n = 4–5/group. (C) Suv420h2 expression in brown and white adipose tissues in 2- to 3-month-old male C57BL/6J mice, n = 4/group. (D and E) Ucp1 (D) and Suv420h2 (E) expression in iWAT of 2- to 3-month-old male C57BL/6J mice during a 5°C cold challenge, n = 10/group in D and n = 4/group in E. (F and G) Ucp1 (F) and Suv420h2 (G) expression during BAT1 brown adipocyte differentiation, n = 4–6/group. (H and I) H4K20 mono-, di-, and trimethylation levels in BAT1 brown adipocytes with scramble siRNA (Control) and Suv420h2 (H2KD) siRNA knockdown (H) or with empty vector (Control) and Suv420h2 (H2OE) overexpression (I), n = 3/group. Blots were run in parallel at the same time. (J and K) Ucp1 expression in BAT1 brown adipocytes with Suv420h2 knockdown (J) or Suv420h2 overexpression (K), n = 4–6/group. (L) Ucp1 expression in BAT1 brown adipocytes with overexpression of empty vector (Control) or Suv420h1 (H1OE), n = 4-5/group. (M–O) Ucp1 (M), Dio2 (N), and Acot2 (O) expression in BAT1 brown adipocytes with Suv420h2 knockdown and further treated with vehicle (dimethyl sulfoxide [DMSO]) or the SUV420H1/H2 inhibitor A196. Four-day differentiated BAT1 cells were treated with scramble or Suv420h2 siRNA via electroporation. On day 6 of differentiation, cells were further treated with DMSO or A196 (5 μM) for 24 hours. Before harvesting, cells were further treated with PBS or NE (1 μm) for 4 hours, n = 3–4/group. Control: Scramble siRNA+DMSO; H2KD: Suv420h2 siRNA+DMSO; H2KD+A196: Suv420h2 siRNA+A196. All data are expressed as mean ± SEM. *P < 0.05 by 1-way ANOVA followed by Tukey’s multiple-comparison test in A–G; *P < 0.05 by unpaired 2-tailed Student’s t test in (H–I); *P < 0.05 by 2-way ANOVA followed by Tukey’s multiple-comparison test in J–L; in M–O, bars with a different letter indicate statistical significance at P < 0.05 as analyzed by 2-way ANOVA followed by Tukey’s multiple-comparison test.