Epigenetic regulation of GABA catabolism in iPSC-derived neurons: The molecular links between FGF21 and histone methylation.
Epigenetic regulation of GABA catabolism in iPSC-derived neurons: The molecular links between FGF21 and histone methylation.
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DOI：
10.1016/j.molmet.2023.101798
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发表时间：
2023-11
影响因子：
8.1
通讯作者：
Weinshilboum, Richard M.
中科院分区：
文献类型：
--
作者：
Ho, Ming-Fen;Zhang, Cheng;Moon, Irene;Biernacka, Joanna;Coombes, Brandon;Ngo, Quyen;Skillon, Cedric;Skime, Michelle;Oesterle, Tyler;Croarkin, Paul E.;Karpyak, Victor M.;Li, Hu;Weinshilboum, Richard M.
成纤维细胞生长因子21（FGF 21）类似物已被测试为物质使用障碍的潜在治疗剂。先前的研究表明，FGF 21可能会影响饮酒和奖励行为。我们最近的报告显示，在酒精使用障碍（AUD）患者中，血浆FGF 21水平与酒精使用呈正相关。FGF 21具有短的半衰期（0.5-2小时）并穿过血脑屏障。因此，我们着手确定诱导多能干细胞（iPSC）衍生的前脑神经元中幼稚形式的FGF 21和长效FGF 21分子（PF-05231023）的分子机制。我们在用生理相关浓度的幼稚FGF 21或PF-05231023处理的iPSC衍生的前脑神经元中进行了RNA-seq。我们从我们先前的AUD临床试验（n = 442）获得了FGF 21和GABA的血浆水平。我们对iPSC衍生的前脑神经元和前脑类器官中的FGF 21进行了ELISA。我们使用免疫共沉淀确定蛋白质相互作用。最后，我们应用ChIP测定法，在有和没有药物暴露的情况下，使用iPSC衍生的前脑神经元，确认FGF 21对REST、EZH 2和H3 K27 me 3的占用。我们分别鉴定了4701个和1956个响应于幼稚FGF 21或PF-05231023的差异表达基因（FDR < 0.05）。值得注意的是，974个差异表达的基因在用幼稚FGF 21和PF-05231023处理之间重叠。REST是差异表达基因最重要的上游调控因子。GABA能突触通路是使用重叠基因鉴定的最重要的通路。我们还观察到AUD患者血浆FGF 21和GABA浓度之间存在显著的正相关。同时，FGF 21和PF-05231023显著诱导iPSC衍生的神经元中的GABA水平。最后，功能基因组学研究表明，药物依赖性占用的REST，EZH 2，和H3 K27 me 3的基因的启动子区域参与GABA catalysts，导致转录抑制。我们的研究结果突出了一个显着的作用，在表观遗传调控的基因参与GABA catalysts相关的FGF 21的行动。(The ClinicalTrials.gov标识符：NCT 00662571）FGF 21类似物可具有作为物质使用障碍的治疗剂的效用。在AUD患者中，FGF 21与GABA水平呈正相关。FGF 21增加iPSC衍生的神经元和脑类器官中的GABA水平。FGF 21介导REST、EZH 2和H3 K27 me 3的占据。REST-EZH 2-H3 K37 me 3复合物以药物依赖性方式介导基因阻遏。
Fibroblast growth factor 21 (FGF21) analogs have been tested as potential therapeutics for substance use disorders. Prior research suggests that FGF21 administration might affect alcohol consumption and reward behaviors. Our recent report showed that plasma FGF21 levels were positively correlated with alcohol use in patients with alcohol use disorder (AUD). FGF21 has a short half-life (0.5–2 h) and crosses the blood–brain barrier. Therefore, we set out to identify molecular mechanisms for both the naïve form of FGF21 and a long-acting FGF21 molecule (PF-05231023) in induced pluripotent stem cell (iPSC)-derived forebrain neurons. We performed RNA-seq in iPSC-derived forebrain neurons treated with naïve FGF21 or PF-05231023 at physiologically relevant concentrations. We obtained plasma levels of FGF21 and GABA from our previous AUD clinical trial (n = 442). We performed ELISA for FGF21 in both iPSC-derived forebrain neurons and forebrain organoids. We determined protein interactions using co-immunoprecipitation. Finally, we applied ChIP assays to confirm the occupancy of REST, EZH2 and H3K27me3 by FGF21 using iPSC-derived forebrain neurons with and without drug exposure. We identified 4701 and 1956 differentially expressed genes in response to naïve FGF21 or PF-05231023, respectively (FDR < 0.05). Notably, 974 differentially expressed genes overlapped between treatment with naïve FGF21 and PF-05231023. REST was the most important upstream regulator of differentially expressed genes. The GABAergic synapse pathway was the most significant pathway identified using the overlapping genes. We also observed a significant positive correlation between plasma FGF21 and GABA concentrations in AUD patients. In parallel, FGF21 and PF-05231023 significantly induced GABA levels in iPSC-derived neurons. Finally, functional genomics studies showed a drug-dependent occupancy of REST, EZH2, and H3K27me3 in the promoter regions of genes involved in GABA catabolism which resulted in transcriptional repression. Our results highlight a significant role in the epigenetic regulation of genes involved in GABA catabolism related to FGF21 action. (The ClinicalTrials.gov Identifier: NCT00662571) FGF21 analogs may have utility as therapeutics for substance use disorders. FGF21 was positively correlated with GABA levels in patients with AUD. FGF21 increased GABA levels in iPSC-derived neurons and brain organoids. FGF21 mediated the occupancy of REST, EZH2 and H3K27me3. The REST-EZH2-H3K37me3 complex mediates gene repression in a drug dependent manner.
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影响因子：
5.6
作者：
通讯作者：
--
影响因子：
--
作者：
Ho, Ming-Fen;Bongartz, Tim;Weinshilboum, Richard M.
通讯作者：
Weinshilboum, Richard M.
影响因子：
64.8
作者：
Collins, Pamela Y.;Patel, Vikram;Joestl, Sarah S.;March, Dana;Insel, Thomas R.;Daar, Abdallah S.
通讯作者：
Daar, Abdallah S.
影响因子：
5.3
作者：
Huang, Hsien-Sung;Matevossian, Anouch;Akbarian, Schahram
通讯作者：
Akbarian, Schahram
DOI：
10.1038/s41386-021-01097-0
发表时间：
2021-11
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
Biernacka JM;Coombes BJ;Batzler A;Ho AM;Geske JR;Frank J;Hodgkinson C;Skime M;Colby C;Zillich L;Pozsonyiova S;Ho MF;Kiefer F;Rietschel M;Weinshilboum R;O'Malley SS;Mann K;Anton R;Goldman D;Karpyak VM
通讯作者：
Karpyak VM