DNMT1 maintains progenitor function in self-renewing somatic tissue.
DNMT1 maintains progenitor function in self-renewing somatic tissue.
复制标题
作者：
祖细胞通过抑制细胞周期退出和终末分化来维持其增殖能力，从而维持组织的自我更新。DNA甲基化为细胞记忆提供了一种潜在的表观遗传机制，这种记忆需要通过重复的细胞分裂来保持体细胞祖细胞状态。DNA甲基转移酶1 （DNMT1）在细胞复制后维持DNA甲基化模式。虽然DNMT1对于胚胎干细胞的维持是必不可少的，但在不断补充的体细胞组织（如哺乳动物表皮）中，DNMT1在维持祖细胞状态方面的明确作用尚不清楚。我们发现DNMT1对表皮祖细胞的功能至关重要。发现DNMT1蛋白在未分化的细胞中富集，在未分化的细胞中需要它来保持增殖耐力和抑制分化。在组织中，DNMT1缺失导致祖细胞室的退出、过早分化和最终的组织损失。全基因组分析显示，表皮分化基因启动子的很大一部分在自我更新条件下甲基化，但随后在分化过程中去甲基化。此外，我们发现UHRF1是DNA甲基化机制的一个组成部分，它将DNMT1靶向半甲基化DNA，也是抑制过早分化和维持增殖所必需的。相比之下，Gadd45A和B促进活跃的DNA去甲基化，是完全表皮分化基因诱导所必需的。这些数据表明，参与DNA甲基化模式动态调节的蛋白质是哺乳动物体细胞组织中祖细胞维持和自我更新所必需的。
Progenitor cells maintain self-renewing tissues throughout life by sustaining their capacity for proliferation while suppressing cell cycle exit and terminal differentiation. DNA methylation provides a potential epigenetic mechanism for the cellular memory needed to preserve the somatic progenitor state through repeated cell divisions. DNA methyltransferase 1 (DNMT1) maintains DNA methylation patterns after cellular replication. Although dispensable for embryonic stem cell maintenance, a clear role for DNMT1 in maintaining the progenitor state in constantly replenished somatic tissues, such as mammalian epidermis, is unknown. Here we show that DNMT1 is essential for epidermal progenitor cell function. DNMT1 protein was found enriched in undifferentiated cells, where it was required to retain proliferative stamina and suppress differentiation. In tissue, DNMT1 depletion led to exit from the progenitor cell compartment, premature differentiation and eventual tissue loss. Genome-wide analysis revealed that a significant portion of epidermal differentiation gene promoters were methylated in self-renewing conditions but were subsequently demethylated during differentiation. Furthermore, we show that UHRF1, a component of the DNA methylation machinery that targets DNMT1 to hemi-methylated DNA, is also necessary to suppress premature differentiation and sustain proliferation. In contrast, Gadd45A and B, which promote active DNA demethylation, are required for full epidermal differentiation gene induction. These data demonstrate that proteins involved in the dynamic regulation of DNA methylation patterns are required for progenitor maintenance and self-renewal in mammalian somatic tissue.
登录
查看更多内容
影响因子：
64.5
作者：
Rai K;Huggins IJ;James SR;Karpf AR;Jones DA;Cairns BR
通讯作者：
Cairns BR
影响因子：
5.3
作者：
Damelin, Marc;Bestor, Timothy H.
通讯作者：
Bestor, Timothy H.
影响因子：
23.9
作者：
Fouse, Shaun D.;Shen, Yin;Fan, Guoping
通讯作者：
Fan, Guoping
影响因子：
56.9
作者：
Bostick, Magnolia;Kim, Jong Kyong;Jacobsen, Steven E.
通讯作者：
Jacobsen, Steven E.
影响因子：
5.6
作者：
BESTOR, T;LAUDANO, A;INGRAM, V
通讯作者：
INGRAM, V