Chromatin changes trigger laminin genes dysregulation in aging kidneys.
Chromatin changes trigger laminin genes dysregulation in aging kidneys.
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DOI：
10.18632/aging.101453
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发表时间：
2018-05-29
期刊：
影响因子：
--
通讯作者：
Bomsztyk K
中科院分区：
文献类型：
--
作者：
Denisenko O;Mar D;Trawczynski M;Bomsztyk K
基因表达失调是衰老的标志。我们研究了介导衰老大鼠肾脏层粘连蛋白基因异常表达的表观遗传机制。在老年动物中，没有发现丰富的层粘连蛋白mRNA水平的变化，而Lama 3，b3和c2转录增加相比，年轻的动物。Lamc 2在mRNA和蛋白水平上表现出最强的变化。Lamc 2上调是转录的，如在该基因的RNA聚合酶II密度升高所示。此外，衰老与Lamc 2基因处的H3 K27 m3和5 mC沉默修饰的丧失相关。蛋白质印迹分析显示，在细胞水平的H3 K27 m3和同源酶Ezh 2在老肾没有变化。因此，Lamc 2处H3 K27 m3的减少是由于该标记在基因组位点之间的重新分布。体外肾细胞研究表明，用Ezh 2抑制剂降低H3 K27 m3密度对Lamc 2表达没有影响，表明这种修饰在衰老肾脏中的基因上调中作用不大。相反，用DNA甲基化抑制剂2 '-脱氧-5-氮杂胞苷处理足以上调Lamc 2基因。我们认为，在沉默层粘连蛋白基因的5 mC的损失驱动他们在衰老过程中的去抑制，有助于与年龄相关的肾功能下降。
Dysregulation of gene expression is a hallmark of aging. We examined epigenetic mechanisms that mediate aberrant expression of laminin genes in aging rat kidneys. In old animals, no alterations were found in the levels of abundant laminin mRNAs, whereas Lama3, b3, and c2 transcripts were increased compared to young animals. Lamc2 showed the strongest changes at the mRNA and protein levels. Lamc2 upregulation was transcriptional, as indicated by the elevated RNA polymerase II density at the gene. Furthermore, aging is associated with the loss of H3K27m3 and 5mC silencing modifications at the Lamc2 gene. Western blot analysis revealed no changes in cellular levels of H3K27m3 and cognate enzyme Ezh2 in old kidneys. Thus, the decrease in H3K27m3 at Lamc2 resulted from the re-distribution of this mark among genomic sites. Studies in kidney cells in vitro showed that reducing H3K27m3 density with Ezh2 inhibitor had no effect on Lamc2 expression, suggesting that this modification plays little role in gene upregulation in aging kidney. In contrast, treatment with DNA methylation inhibitor 2'-deoxy-5-azacytidine was sufficient to upregulate Lamc2 gene. We suggest that the loss of 5mC at silenced laminin genes drives their de-repression during aging, contributing to the age-related decline in renal function.
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DOI：
10.1016/j.bbagrm.2016.04.001
发表时间：
2016-07
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Denisenko O;Lucas ES;Sun C;Watkins AJ;Mar D;Bomsztyk K;Fleming TP
通讯作者：
Fleming TP
影响因子：
10.5
作者：
Barradas, Marta;Anderton, Emma;Gil, Jesus
通讯作者：
Gil, Jesus
影响因子：
10.5
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian
影响因子：
3.2
作者：
Kainulainen, T;Häkkinen, L;Oikarinen, A
通讯作者：
Oikarinen, A
影响因子：
15.9
作者：
LARJAVA, H;SALO, T;HEINO, J
通讯作者：
HEINO, J