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人乳腺上皮细胞恶性转化过程中MBD2在甲基化DNA区域沉积的动力学

Dynamics of MBD2 deposition across methylated DNA regions during malignant transformation of human mammary epithelial cells.

作者信息

Devailly Guillaume, Grandin Mélodie, Perriaud Laury, Mathot Pauline, Delcros Jean-Guy, Bidet Yannick, Morel Anne-Pierre, Bignon Jean-Yves, Puisieux Alain, Mehlen Patrick, Dante Robert

机构信息

Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.

Institut Curie and INSERM U612, Centre Universitaire, 91405, Orsay, France.

出版信息

Nucleic Acids Res. 2015 Jul 13;43(12):5838-54. doi: 10.1093/nar/gkv508. Epub 2015 May 24.

DOI:10.1093/nar/gkv508
PMID:26007656
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4499136/
Abstract

DNA methylation is thought to induce transcriptional silencing through the combination of two mechanisms: the repulsion of transcriptional activators unable to bind their target sites when methylated, and the recruitment of transcriptional repressors with specific affinity for methylated DNA. The Methyl CpG Binding Domain proteins MeCP2, MBD1 and MBD2 belong to the latter category. Here, we present MBD2 ChIPseq data obtained from the endogenous MBD2 in an isogenic cellular model of oncogenic transformation of human mammary cells. In immortalized (HMEC-hTERT) or transformed (HMLER) cells, MBD2 was found in a large proportion of methylated regions and associated with transcriptional silencing. A redistribution of MBD2 on methylated DNA occurred during oncogenic transformation, frequently independently of local DNA methylation changes. Genes downregulated during HMEC-hTERT transformation preferentially gained MBD2 on their promoter. Furthermore, depletion of MBD2 induced an upregulation of MBD2-bound genes methylated at their promoter regions, in HMLER cells. Among the 3,160 genes downregulated in transformed cells, 380 genes were methylated at their promoter regions in both cell lines, specifically associated by MBD2 in HMLER cells, and upregulated upon MBD2 depletion in HMLER. The transcriptional MBD2-dependent downregulation occurring during oncogenic transformation was also observed in two additional models of mammary cell transformation. Thus, the dynamics of MBD2 deposition across methylated DNA regions was associated with the oncogenic transformation of human mammary cells.

摘要

DNA甲基化被认为通过两种机制的结合诱导转录沉默：一是当甲基化时排斥无法结合其靶位点的转录激活因子；二是募集对甲基化DNA具有特异性亲和力的转录抑制因子。甲基化CpG结合域蛋白MeCP2、MBD1和MBD2属于后者。在此，我们展示了从人乳腺细胞致癌转化的同基因细胞模型中的内源性MBD2获得的MBD2染色质免疫沉淀测序（ChIPseq）数据。在永生化（HMEC-hTERT）或转化（HMLER）细胞中，发现MBD2存在于大部分甲基化区域并与转录沉默相关。在致癌转化过程中，MBD2在甲基化DNA上发生了重新分布，这一过程常常独立于局部DNA甲基化变化。在HMEC-hTERT转化过程中下调的基因在其启动子上优先获得MBD2。此外，在HMLER细胞中，MBD2的缺失诱导了其结合的、启动子区域甲基化的基因上调。在转化细胞中下调的3160个基因中，有380个基因在两种细胞系的启动子区域均发生甲基化，在HMLER细胞中与MBD2特异性结合，并在HMLER细胞中MBD2缺失后上调。在另外两种乳腺细胞转化模型中也观察到了致癌转化过程中发生的依赖于MBD2的转录下调。因此，MBD2在甲基化DNA区域沉积的动态变化与人类乳腺细胞的致癌转化相关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/afc1cda2548e/gkv508fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/3f31cffd262a/gkv508fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/b549509b8928/gkv508fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/0845ec07d52f/gkv508fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/4418fbf5d72c/gkv508fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/8f75203068e2/gkv508fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/afc1cda2548e/gkv508fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/3f31cffd262a/gkv508fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/b549509b8928/gkv508fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/0845ec07d52f/gkv508fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/4418fbf5d72c/gkv508fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/8f75203068e2/gkv508fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04a5/4499136/afc1cda2548e/gkv508fig7.jpg

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