Long term transcriptional reactivation of epigenetically silenced genes in colorectal cancer cells requires DNA hypomethylation and histone acetylation.
Long term transcriptional reactivation of epigenetically silenced genes in colorectal cancer cells requires DNA hypomethylation and histone acetylation.
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DOI：
10.1371/journal.pone.0023127
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Scott RJ
中科院分区：
文献类型：
--
作者：
Mossman D;Scott RJ
基因的表观遗传调控涉及DNA甲基化和组蛋白修饰的协调以维持转录状态。这两个特征在恶性肿瘤中经常被破坏，使得关键基因屈服于失活。5-氮杂-2 ′-脱氧胞苷（5-aza-dC）是一种抑制DNA甲基转移酶的药物，具有治疗癌症的巨大潜力，但其有效性在不同肿瘤类型之间存在很大差异。以前的证据表明，5-aza-dC暴露后的表达状态不能单独用DNA甲基化状态来解释。我们试图确定染色质的变化涉及短期和长期的基因再激活后5-氮杂-dC曝光。用5-aza-dC处理两种结肠直肠癌细胞系HCT 116和SW 480，然后在无药物培养基中生长以允许DNA再甲基化。用亚硫酸氢盐测序和染色质免疫沉淀分析评估DNA甲基化和染色质修饰。增加H3乙酰化，H3 K4三甲基化和H3 K27三甲基化的损失与再活化相关。未显示乙酰化增加的高甲基化基因在恢复到非活性状态之前用5-aza-dC处理瞬时表达。三个重新激活的基因，CDO 1，HSPC 105和MAGEA 3，在5-aza-dC处理后10天仍然表达，并在转录起始位点显示局部低甲基化，以及组蛋白H3乙酰化的增加富集。这些观察结果表明，单独的低甲基化不足以重新激活沉默的基因，并且增加的组蛋白H3乙酰化与局部低甲基化一致允许这些表观遗传学沉默的基因的长期逆转。这项研究表明，结合DNA甲基转移酶和组蛋白脱乙酰酶抑制剂可能有助于长期重新激活沉默的基因。
Epigenetic regulation of genes involves the coordination of DNA methylation and histone modifications to maintain transcriptional status. These two features are frequently disrupted in malignancy such that critical genes succumb to inactivation. 5-aza-2′-deoxycytidine (5-aza-dC) is an agent which inhibits DNA methyltransferase, and holds great potential as a treatment for cancer, yet the extent of its effectiveness varies greatly between tumour types. Previous evidence suggests expression status after 5-aza-dC exposure cannot be explained by the DNA methylation status alone. We sought to identify chromatin changes involved with short and long term gene reactivation following 5-aza-dC exposure. Two colorectal cancer cell lines, HCT116 and SW480, were treated with 5-aza-dC and then grown in drug-free media to allow DNA re-methylation. DNA methylation and chromatin modifications were assessed with bisulfite sequencing and Chromatin Immuno-Precipitation analysis. Increased H3 acetylation, H3K4 tri-methylation and loss of H3K27 tri-methylation were associated with reactivation. Hypermethylated genes that did not show increased acetylation were transiently expressed with 5-aza-dC treatment before reverting to an inactive state. Three reactivated genes, CDO1, HSPC105 and MAGEA3, were still expressed 10 days post 5-aza-dC treatment and displayed localised hypomethylation at the transcriptional start site, and also an increased enrichment of histone H3 acetylation. These observations suggest that hypomethylation alone is insufficient to reactivate silenced genes and that increased Histone H3 acetylation in unison with localised hypomethylation allows long term reversion of these epigenetically silenced genes. This study suggests that combined DNA methyltransferase and histone deacetylase inhibitors may aid long term reactivation of silenced genes.
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DOI：
10.1158/1078-0432.ccr-09-0401
发表时间：
2009-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Baba Y;Nosho K;Shima K;Freed E;Irahara N;Philips J;Meyerhardt JA;Hornick JL;Shivdasani RA;Fuchs CS;Ogino S
通讯作者：
Ogino S
影响因子：
11.5
作者：
Deng, Guoren;Kakar, Sanjay;Kim, Young S.
通讯作者：
Kim, Young S.
DOI：
10.1073/pnas.101617298
发表时间：
2001-04-24
影响因子：
11.1
作者：
Magdinier, F;Wolffe, AP
通讯作者：
Wolffe, AP
影响因子：
4
作者：
Mitchell, C. M.;Johnson, R. F.;Zakar, T.
通讯作者：
Zakar, T.
影响因子：
37.3
作者：
Menendez, Laura;Walker, DeEtte;Matyunina, Lilya V.;Dickerson, Erin B.;Bowen, Nathan J.;Polavarapu, Nalini;Benigno, Benedict B.;McDonald, John F.
通讯作者：
McDonald, John F.