TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program.
TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program.
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DOI：
10.1371/journal.pgen.0040010
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发表时间：
2008-01
期刊：
影响因子：
4.5
通讯作者：
Artandi SE
中科院分区：
文献类型：
--
作者：
Choi J;Southworth LK;Sarin KY;Venteicher AS;Ma W;Chang W;Cheung P;Jun S;Artandi MK;Shah N;Kim SK;Artandi SE
端粒酶在干细胞功能和组织稳态中发挥着关键作用。这种作用取决于其合成端粒重复序列的能力，其方式依赖于其蛋白组分端粒酶RT（TERT）的逆转录酶（RT）功能，以及一种新的途径，其机制知之甚少。在这里，我们使用一个缺乏逆转录酶功能的突变体（TERTci）来研究哺乳动物皮肤中的TERT作用机制，皮肤是研究祖细胞生物学的理想组织。我们发现，TERTci保留了野生型TERT在增强皮肤角质形成细胞增殖和激活静息毛囊干细胞方面的全部活性，这触发了新毛囊生长阶段的启动并促进毛发合成。为了了解这种非RT依赖性的TERT功能的性质，我们研究了小鼠皮肤中TERT水平急性变化的全基因组转录反应。我们发现，TERT通过触发基因表达的快速变化促进皮肤和毛囊中祖细胞的激活，该基因表达与野生型小鼠中控制自然毛囊周期的程序显著重叠。使用模式匹配算法与其他微阵列基因集的统计学比较显示，TERT转录反应与Myc和Wnt介导的转录反应非常相似，这两种蛋白质与干细胞功能和癌症密切相关。这些数据表明，TERT控制组织祖细胞通过转录调控的发展计划，收敛于Myc和Wnt途径。组织内的干细胞和祖细胞需要维持组织稳态并通过产生分化的子细胞来修复损伤后的组织。许多祖细胞表达端粒酶，这是一种逆转录酶，可以将DNA重复序列添加到端粒上，端粒是染色体末端的保护结构。通过端粒酶添加端粒对于正常祖细胞功能是重要的，并且对于使癌细胞能够无限次分裂至关重要。端粒酶逆转录酶（telomerase reverse transcriptase，TERT）除了具有延长端粒的功能外，还可以直接激活静止的表皮干细胞。然而，这种新的功能的机制，为TERT仍然不清楚。在这项研究中，我们证明了TERT的催化活性是其在体内激活组织祖细胞的能力。此外，使用基因微阵列，我们表明，端粒酶逆转录酶控制的发展计划，重叠的自然转录程序的毛囊周期在小鼠皮肤。使用模式匹配算法，我们发现TERT控制的遗传程序与Myc和Wnt调控的程序非常相似，Myc和Wnt是干细胞功能和肿瘤发生的两个关键途径。本文揭示了关键的新的见解，非端粒酶功能的新机制的端粒酶，确定端粒酶作为一个发育调节器连接到控制转录反应。
Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERTci) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERTci retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways. Stem cells and progenitor cells within a tissue are required to maintain tissue homeostasis and to repair tissues after injury by giving rise to differentiated daughter cells. Many progenitor cells express telomerase, a reverse transcriptase enzyme that adds DNA repeats to telomeres, the protective structures that cap chromosome ends. Telomere addition by telomerase is important for normal progenitor cell function and is crucial for enabling cancer cells to divide an unlimited number of times. In addition to its telomere-lengthening function, telomerase reverse transcriptase (TERT) can directly activate quiescent epidermal stem cells. However, the mechanism underlying this novel function for TERT is still not understood. In this study, we demonstrate that the catalytic activity of TERT is dispensable for its ability to activate tissue progenitor cells in vivo. Furthermore, using gene microarrays, we show that TERT controls a developmental program that overlaps the natural transcriptional program of hair follicle cycling in mouse skin. Using pattern-matching algorithms, we find that the TERT-controlled genetic program significantly resembles programs regulated by Myc and Wnt, two pathways critical for stem cell function and tumorigenesis. This paper reveals critical new insights into novel mechanisms of non-telomerase functions of TERT, identifying TERT as a developmental regulator linked to control of transcriptional responses.
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