Epigenetic changes play critical role in age-associated dysfunctions of the liver.
Epigenetic changes play critical role in age-associated dysfunctions of the liver.
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DOI：
10.1111/j.1474-9726.2010.00617.x
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发表时间：
2010-10
期刊：
影响因子：
7.8
通讯作者：
Timchenko NA
中科院分区：
文献类型：
--
作者：
Jin J;Wang GL;Iakova P;Shi X;Haefliger S;Finegold M;Timchenko NA
C/EBP家族蛋白是肝脏功能的重要调节因子。在这里，我们展示了C/ ebp α-介导的染色质重塑在与年龄相关的肝脏功能障碍和维持生理稳态中的关键作用。由于C/EBPα的ph-S193亚型在老年小鼠肝脏中增加，我们产生了C/EBPα- s193d敲入小鼠，模拟C/EBPα的ph-S193亚型。对这些小鼠的分析表明，S193D突变引起染色质重塑，导致“病灶样”结节的组织学外观，这也在老年小鼠的肝脏中观察到。这些“病灶样”结构含有K9三甲基化组蛋白H3，这是一种异染色质标记。S193D小鼠异染色质区域的增加与S193D- c /EBPα-HDAC1复合物的升高以及细胞周期蛋白D1和D2启动子的表观遗传沉默和肝脏增殖抑制等基因表达失调有关。抑制HDAC1可消除S193D小鼠C/EBPα-HDAC1复合物，纠正染色质结构，使细胞周期蛋白D1和D2的表达正常化。我们发现，S193D小鼠的表观遗传失调也与C/EBPβ的升高和C/EBPα/β异源二聚体的增加有关。C/EBPα/β异二聚体激活Glut4的转录并增加Glut4的水平。因此，S193D肝加速了葡萄糖的摄取和肝中糖原的积累。因此，本研究表明，C/EBPα在S193位点的磷酸化导致异染色质区域的出现，而异染色质区域与肝脏年龄相关功能障碍的发展有关。
C/EBP family proteins are important regulators of liver functions. Here we show the critical role of C/EBPα-mediated chromatin remodeling in the age-associated dysfunctions of the liver and in the maintenance of physiological homeostasis. Because ph-S193 isoform of C/EBPα is increased in livers of old mice, we have generated C/EBPα-S193D knockin mice which mimic the ph-S193 isoform of C/EBPα. Analyses of these mice showed that the S193D mutation causes chromatin remodeling leading to histological appearance of “foci-like” nodules, which are also observed in livers of old mice. These “foci–like” structures contain K9 thrimethylated histone H3, a marker of heterochromatin. The increase of heterochromatin regions in S193D mice correlates with the elevation of S193D-C/EBPα-HDAC1 complexes and with dys-regulation of gene expression including epigenetic silencing of cyclin D1 and D2 promoters and the inhibition of liver proliferation. The elimination of C/EBPα-HDAC1 complexes in S193D mice by inhibition of HDAC1 corrects chromatin structure and normalizes expression of cyclin D1 and D2. We found that epigenetic dys-regulation is also associated with the elevation of C/EBPβ and with the increase of C/EBPα/β hetero-dimers in S193D mice. The C/EBPα/β hetero-dimers activate transcription of Glut4 and increase levels of Glut4. As the result, S193D livers have accelerated uptake of glucose and accumulation of glycogen in the liver. Thus, this study demonstrates that phosphorylation of C/EBPα at S193 leads to the appearance of heterochromatin regions which correlates with the development of age-related dysfunctions of the liver.
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DOI：
10.18632/aging.100060
发表时间：
2009-06-22
期刊：
Aging
影响因子：
--
作者：
Jin J;Wang GL;Timchenko L;Timchenko NA
通讯作者：
Timchenko NA
影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
影响因子：
13.5
作者：
Corbin, IR;Buist, R;Minuk, GY
通讯作者：
Minuk, GY
影响因子：
64.8
作者：
Conboy, IM;Conboy, MJ;Rando, TA
通讯作者：
Rando, TA
影响因子：
5.3
作者：
Timchenko, NA;Harris, TE;Darlington, GJ
通讯作者：
Darlington, GJ