A thyroid hormone receptor/KLF9 axis in human hepatocytes and pluripotent stem cells.
A thyroid hormone receptor/KLF9 axis in human hepatocytes and pluripotent stem cells.
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DOI：
10.1002/stem.1875
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Webb P
中科院分区：
文献类型：
--
作者：
Cvoro A;Devito L;Milton FA;Noli L;Zhang A;Filippi C;Sakai K;Suh JH;H Sieglaff D;Dhawan A;Sakai T;Ilic D;Webb P
生物过程需要整合不同信号的多个转录因子的密切合作。甲状腺激素受体（TRs）诱导Krüppel样因子9（KLF 9）调节神经发生。在这里，我们表明，三碘甲腺原氨酸（T3）也通过TR诱导KLF 9在HepG 2肝细胞，小鼠肝脏，小鼠和人的原代肝细胞，并试图了解TR/KLF 9在肝细胞谱系和干细胞的网络功能。敲除实验表明，KLF 9调节数百个HepG 2靶基因并调节T3反应。T3和KLF 9靶基因共同影响干细胞自我更新和分化中涉及的途径，包括Notch信号传导，我们验证了T3和KLF 9合作调节关键的Notch途径基因，并独立调节其他基因。T3还诱导人胚胎干细胞（hESC）和人诱导多能干细胞（hiPSC）中的KLF 9，并且这种作用在分化为定形内胚层和hiPSC衍生的肝细胞期间持续存在。微阵列分析显示，T3调节数百个hESC和hiPSC靶基因，这些靶基因聚集到HepG 2细胞中涉及TR和KLF 9调节的许多相同途径中。KLF 9敲低证实TR和KLF 9协同调节hESC和hiPSC中的Notch途径基因，尽管是以部分细胞特异性方式。对T3应答性hESC/hiPSC基因的更广泛分析表明TR调节ESC分化中的多个早期步骤。我们认为TRs与KLF 9共同调控肝细胞的增殖、分化和器官形成的早期阶段，TRs对ESC生物学产生广泛而重要的影响。
Biological processes require close cooperation of multiple transcription factors that integrate different signals. Thyroid hormone receptors (TRs) induce Krüppel-like factor 9 (KLF9) to regulate neurogenesis. Here, we show that triiodothyronine (T3) also works through TR to induce KLF9 in HepG2 liver cells, mouse liver, and mouse and human primary hepatocytes and sought to understand TR/KLF9 network function in the hepatocyte lineage and stem cells. Knockdown experiments reveal that KLF9 regulates hundreds of HepG2 target genes and modulates T3 response. Together, T3 and KLF9 target genes influence pathways implicated in stem cell self-renewal and differentiation, including Notch signaling, and we verify that T3 and KLF9 cooperate to regulate key Notch pathway genes and work independently to regulate others. T3 also induces KLF9 in human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSC) and this effect persists during differentiation to definitive endoderm and hiPSC-derived hepatocytes. Microarray analysis reveals that T3 regulates hundreds of hESC and hiPSC target genes that cluster into many of the same pathways implicated in TR and KLF9 regulation in HepG2 cells. KLF9 knockdown confirms that TR and KLF9 cooperate to regulate Notch pathway genes in hESC and hiPSC, albeit in a partly cell-specific manner. Broader analysis of T3 responsive hESC/hiPSC genes suggests that TRs regulate multiple early steps in ESC differentiation. We propose that TRs cooperate with KLF9 to regulate hepatocyte proliferation and differentiation and early stages of organogenesis and that TRs exert widespread and important influences on ESC biology.
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