SETDB2 Links Glucocorticoid to Lipid Metabolism through Insig2a Regulation.
SETDB2 Links Glucocorticoid to Lipid Metabolism through Insig2a Regulation.
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DOI：
10.1016/j.cmet.2016.07.025
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发表时间：
2016-09-13
期刊：
影响因子：
29
通讯作者：
Osborne TF
中科院分区：
文献类型：
--
作者：
Roqueta-Rivera M;Esquejo RM;Phelan PE;Sandor K;Daniel B;Foufelle F;Ding J;Li X;Khorasanizadeh S;Osborne TF
转录和染色质调节介导肝脏对营养可用性的反应。染色质因子在响应禁食的激素调节中的作用还没有完全了解。我们已经确定了SETDB 2，糖皮质激素诱导的推定的表观遗传修饰剂，作为GR介导的基因激活在肝脏中的正调节。Insig 2a在禁食期间增加以限制脂质合成，但诱导机制尚不清楚。我们表明Insig 2a诱导是GR-SETDB 2依赖性的。SETDB 2促进GR染色质富集，是糖皮质激素依赖性增强子-启动子相互作用的关键。INSIG 2是SREBP的负调节因子，急性糖皮质激素治疗降低了Ob/Ob小鼠再喂养期间或肝脏中的活性SREBP;两种升高的SREBP-1c系统都驱动脂肪生成。敲低SETDB 2或INSIG 2逆转了对活性SREBP的抑制。总体而言，这些研究确定了肝脏转录重编程的GR-SETDB 2调节轴，并将SETDB 2确定为具有异常糖皮质激素作用的代谢紊乱的潜在靶点。XXX等人鉴定了SETDB 2（赖氨酸甲基转移酶SET结构域家族的成员）在肝脏禁食期间糖皮质激素受体（GR）介导的基因激活的新型潜在调节机制中的作用。肝脏转录重编程的GR-SETDB 2调节轴与糖皮质激素作用异常的代谢紊乱相关。
Transcriptional and chromatin regulations mediate the liver response to nutrient availability. The role of chromatin factors involved in hormonal regulation in response to fasting is not fully understood. We have identified SETDB2, a glucocorticoid-induced putative epigenetic modifier, as a positive regulator of GR-mediated gene activation in liver. Insig2a increases during fasting to limit lipid synthesis, but the mechanism of induction is unknown. We show Insig2a induction is GR-SETDB2-dependent. SETDB2 facilitates GR chromatin enrichment and is key to glucocorticoid dependent enhancer-promoter interactions. INSIG2 is a negative regulator of SREBP and acute glucocorticoid treatment decreased active SREBP during refeeding or in livers of Ob/Ob mice; both systems of elevated SREBP-1c driven lipogenesis. Knockdown of SETDB2 or INSIG2 reversed the inhibition on active SREBPs. Overall, these studies identify a GR-SETDB2 regulatory axis of hepatic transcriptional reprogramming and identify SETDB2 as a potential target for metabolic disorders with aberrant glucocorticoid actions. XXX et al identify SETDB2, a member of the SET-domain family of lysine Methyltransferases, in a novel underlying regulatory mechanism for glucocorticoid receptor (GR)-mediated gene activation during fasting in the liver. This GR-SETDB2 regulatory axis of hepatic transcriptional reprogramming is relevant to metabolic disorders with aberrant glucocorticoid actions.
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影响因子：
16.6
作者：
Abe, Yohei;Rozqie, Royhan;Matsumura, Yoshihiro;Kawamura, Takeshi;Nakaki, Ryo;Tsurutani, Yuya;Tanimura-Inagaki, Kyoko;Shiono, Akira;Magoori, Kenta;Nakamura, Kanako;Ogi, Shotaro;Kajimura, Shingo;Kimura, Hiroshi;Tanaka, Toshiya;Fukami, Kiyoko;Osborne, Timothy F.;Kodama, Tatsuhiko;Aburatani, Hiroyuki;Inagaki, Takeshi;Sakai, Juro
通讯作者：
Sakai, Juro
影响因子：
6.7
作者：
Kroetz DN;Allen RM;Schaller MA;Cavallaro C;Ito T;Kunkel SL
通讯作者：
Kunkel SL
DOI：
10.1073/pnas.95.11.5987
发表时间：
1998-05-26
影响因子：
11.1
作者：
Horton, JD;Bashmakov, Y;Shimano, H
通讯作者：
Shimano, H
影响因子：
--
作者：
Lee, Seunghee;Lee, Jeongkyung;Lee, Jae W.
通讯作者：
Lee, Jae W.
影响因子：
4.6
作者：
Glaser, S;Schaft, J;Stewart, AF
通讯作者：
Stewart, AF