Epigenetic Reprogramming of Lineage-Committed Human Mammary Epithelial Cells Requires DNMT3A and Loss of DOT1L
Epigenetic Reprogramming of Lineage-Committed Human Mammary Epithelial Cells Requires DNMT3A and Loss of DOT1L
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DOI：
10.1016/j.stemcr.2017.06.019
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发表时间：
2017-09-12
影响因子：
5.9
通讯作者：
Kuperwasser, Charlotte
中科院分区：
文献类型：
--
作者：
Breindel, Jerrica L.;Skibinski, Adam;Kuperwasser, Charlotte
器官发生和组织发育通过连续的逐步过程发生，导致谱系限制增加和多能性丧失。一个例外出现在成人乳腺，罕见的变异上皮细胞表现出多能性和多系分化潜力时，从他们的天然微环境的信号。这种现象提供了一个独特的机会，研究机制，导致细胞重编程和谱系可塑性在真实的时间。在这里，我们表明，原代人乳腺上皮细胞（HMEC）失去表达的方式依赖于旁分泌因子和表观遗传调控的分化乳腺上皮标志物。此外，我们证明，HMEC重编程依赖于DNA甲基转移酶DNMT3A的基因沉默和甲基转移酶DOT1L下调后组蛋白转录标记的丢失。这些结果表明，成体组织中的谱系定型是背景依赖性的，并突出了体细胞从其天然组织微环境中移除时的可塑性。
Organogenesis and tissue development occur through sequential stepwise processes leading to increased lineage restriction and loss of pluripotency. An exception to this appears in the adult human breast, where rare variant epithelial cells exhibit pluripotency and multilineage differentiation potential when removed from the signals of their native microenvironment. This phenomenon provides a unique opportunity to study mechanisms that lead to cellular reprogramming and lineage plasticity in real time. Here, we show that primary humanmammary epithelial cells (HMECs) lose expression of differentiated mammary epithelial markers in a manner dependent on paracrine factors and epigenetic regulation. Furthermore, we demonstrate that HMEC reprogramming is dependent on gene silencing by the DNA methyltransferase DNMT3A and loss of histone transcriptional marks following downregulation of the methyltransferase DOT1L. These results demonstrate that lineage commitment in adult tissues is context dependent and highlight the plasticity of somatic cells when removed from their native tissue microenvironment.