PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation.
PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation.
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DOI：
10.1186/gb-2013-14-9-r99
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发表时间：
2013
期刊：
影响因子：
12.3
通讯作者：
Ballestar E
中科院分区：
文献类型：
--
作者：
de la Rica L;Rodríguez-Ubreva J;García M;Islam AB;Urquiza JM;Hernando H;Christensen J;Helin K;Gómez-Vaquero C;Ballestar E
DNA甲基化是驱动和稳定细胞命运决定的关键表观遗传机制。DNA甲基化的局部沉积和去除与转录因子的结合密切相关，尽管这种关系因特定的分化过程而异。单核细胞向破骨细胞的转化是造血系统中一个独特的终末分化过程。这种分化模式与自身免疫性疾病和癌症有关，并且关于涉及的转录因子集合有丰富的知识。在这里，我们重点研究破骨细胞形成过程中DNA甲基化的变化。数千个基因发生了高甲基化和低甲基化变化，包括所有相关的破骨细胞分化和功能类别。低甲基化与5-羟甲基胞嘧啶的变化有关，5-羟甲基胞嘧啶是一种被认为是去甲基化的中间体。转录因子结合基序分析表明，PU1、NF-κB和AP-1(Jun/Fos)结合基序在发生甲基化变化的基因中过度表达。其中，只有PU.1基序显著富含高甲基化和低甲基化基因；CHIP-SEQ数据分析证实了它与这两个基因集的关联。此外，PU.1与Dnmt3b和TET2都有相互作用，提示它参与了驱动超甲基化和羟甲基化介导的低甲基化。与此一致的是，在破骨细胞分化过程中，siRNA介导的PU1基因敲除削弱了DNA甲基化的获得和表达的变化，并减少了PU1靶点TET2和Dnmt3b的关联。这里描述的工作确定了单核细胞到破骨细胞分化过程中DNA甲基化的关键变化，并揭示了PU.1在这一过程中的新角色。
DNA methylation is a key epigenetic mechanism for driving and stabilizing cell-fate decisions. Local deposition and removal of DNA methylation are tightly coupled with transcription factor binding, although the relationship varies with the specific differentiation process. Conversion of monocytes to osteoclasts is a unique terminal differentiation process within the hematopoietic system. This differentiation model is relevant to autoimmune disease and cancer, and there is abundant knowledge on the sets of transcription factors involved. Here we focused on DNA methylation changes during osteoclastogenesis. Hypermethylation and hypomethylation changes took place in several thousand genes, including all relevant osteoclast differentiation and function categories. Hypomethylation occurred in association with changes in 5-hydroxymethylcytosine, a proposed intermediate toward demethylation. Transcription factor binding motif analysis revealed an over-representation of PU.1, NF-κB, and AP-1 (Jun/Fos) binding motifs in genes undergoing DNA methylation changes. Among these, only PU.1 motifs were significantly enriched in both hypermethylated and hypomethylated genes; ChIP-seq data analysis confirmed its association to both gene sets. Moreover, PU.1 interacts with both DNMT3b and TET2, suggesting its participation in driving hypermethylation and hydroxymethylation-mediated hypomethylation. Consistent with this, siRNA-mediated PU.1 knockdown in primary monocytes impaired the acquisition of DNA methylation and expression changes, and reduced the association of TET2 and DNMT3b at PU.1 targets during osteoclast differentiation. The work described here identifies key changes in DNA methylation during monocyte-to-osteoclast differentiation and reveals novel roles for PU.1 in this process.
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DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
12.3
作者：
Hernando, Henar;Shannon-Lowe, Claire;Ballestar, Esteban
通讯作者：
Ballestar, Esteban
影响因子：
5.8
作者：
Al-Shahrour, F;Díaz-Uriarte, R;Dopazo, J
通讯作者：
Dopazo, J
影响因子：
7
作者：
Hogart A;Lichtenberg J;Ajay SS;Anderson S;NIH Intramural Sequencing Center;Margulies EH;Bodine DM
通讯作者：
Bodine DM
影响因子：
16
作者：
Kallin, Eric M.;Rodriguez-Ubreva, Javier;Christensen, Jesper;Cimmino, Luisa;Aifantis, Iannis;Helin, Kristian;Ballestar, Esteban;Graf, Thomas
通讯作者：
Graf, Thomas