Unique ERα Cistromes Control Cell Type-Specific Gene Regulation
Unique ERα Cistromes Control Cell Type-Specific Gene Regulation
复制标题
DOI：
10.1210/me.2008-0100
复制
发表时间：
2008-11-01
影响因子：
--
通讯作者：
Brown, Myles
中科院分区：
文献类型：
--
作者：
Krum, Susan A.;Miranda-Carboni, Gustavo A.;Brown, Myles
雌激素在正常生理和涉及不同组织（包括乳腺和骨骼）的各种病理状态中发挥重要作用。然而，雌激素发挥细胞类型和疾病特异性作用的机制仍有待解释。我们比较了基因表达谱的MCF 7乳腺癌细胞系与成骨细胞样细胞系U2 OS-ER α的表达芯片。我们发现，17个β-雌二醇（E2）调节基因中只有不到10%是两种细胞类型共有的。我们已经在原代颅骨成骨细胞中证实了这一点。为了剖析MCF 7和U2 OS-ER α细胞中基因表达的细胞类型特异性E2调节的潜在机制，我们通过在基因组平铺阵列（ChIP芯片）上进行染色质免疫沉淀（ChIP）来比较两种细胞类型中DNA上的ER α结合位点。与这两种细胞系中E2调节基因表达的不同模式一致，我们发现绝大多数ER α结合位点也是细胞类型特异性的，并且在位置和数量上与细胞类型特异性基因调控相关。有趣的是，尽管叉头因子FoxA 1在确定MCF 7细胞中的ER α顺式组中起关键作用，但它在U2 OS-ER α细胞中不表达，并且叉头基序在这些细胞中的ER α顺式组中不富集。最后，ER α顺反序列与细胞类型特异性表观遗传组蛋白修饰相关。这些结果支持E2的细胞类型特异性作用的模型，其主要通过靶基因的表观遗传标记的顺式调节区的特异性ER α占据来驱动。（分子内分泌学22：2393-2406，2008）
Estrogens play an important role in normal physiology and in a variety of pathological states involving diverse tissues including breast and bone. The mechanism by which estrogens exert cell type- and disease-specific effects, however, remains to be explained. We have compared the gene expression profile of the MCF7 breast cancer cell line with that of the osteoblast-like cell line U2OS-ER alpha by expression microarrays. We find that fewer than 10% of the 17 beta-estradiol (E2)-regulated genes are common to both cell types. We have validated this in primary calvarial osteoblasts. To dissect the mechanism underlying the cell type- specific E2 regulation of gene expression in MCF7 and U2OS-ER alpha cells, we compared the ER alpha binding sites on DNA in the two cell types by performing chromatin immunoprecipitation (ChIP) on genomic tiling arrays (ChIP-on-chip). Consistent with the distinct patterns of E2-regulated gene expression in these two cell lines, we find that the vast majority of ER alpha binding sites are also cell type specific and correlate both in position and number with cell type-specific gene regulation. Interestingly, although the forkhead factor FoxA1 plays a critical role in defining the ER alpha cistrome in MCF7 cells, it is not expressed in U2OS-ER alpha cells, and forkhead motifs are not enriched in the ER alpha cistrome in these cells. Finally, the ER alpha cistromes are correlated with cell type- specific epigenetic histone modifications. These results support a model for the cell type-specific action of E2 being driven primarily through specific ER alpha occupancy of epigenetically marked cis-regulatory regions of target genes. (Molecular Endocrinology 22: 2393-2406, 2008)