RIKEN Cluster for Pioneering Research, Tsukuba, Ibaraki 305-0074, Japan.
Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
Nucleic Acids Res. 2019 Jan 10;47(1):283-298. doi: 10.1093/nar/gky1149.
Various stresses increase disease susceptibility and accelerate aging, and increasing evidence suggests that these effects can be transmitted over generation. Epidemiological studies suggest that stressors experienced by parents affect the longevity of their offspring, possibly by regulating telomere dynamics. Telomeres are elongated by telomerase and shortened by certain stresses as well as telomere repeat-containing RNA (TERRA), a telomere transcript. However, the mechanism underlying the transgenerational effects is poorly understood. Here, we show that TNF-α, which is induced by various psychological stresses, induces the p38-dependent phosphorylation of ATF7, a stress-responsive chromatin regulator, in mouse testicular germ cells. This caused a release of ATF7 from the TERRA gene promoter in the subtelomeric region, which disrupted heterochromatin and induced TERRA. TERRA was transgenerationally transmitted to zygotes via sperm and caused telomere shortening. These results suggest that ATF7 and TERRA play key roles in paternal stress-induced telomere shortening in the offspring.
各种压力会增加疾病易感性并加速衰老，越来越多的证据表明，这些效应可以在代际间传递。流行病学研究表明，父母经历的压力因素会影响其后代的寿命，这可能是通过调节端粒动力学实现的。端粒酶可使端粒延长，某些压力以及含有端粒重复序列的 RNA（TERRA），即端粒转录本，会使端粒缩短。然而，代际效应的机制尚不清楚。本文中，作者发现，多种心理压力诱导的 TNF-α会导致应激反应性染色质调节剂 ATF7 发生 p38 依赖性磷酸化，从而导致端粒区附近的 TERRA 基因启动子上的 ATF7 释放，破坏异染色质并诱导 TERRA。TERRA 通过精子在世代间传递，并导致端粒缩短。这些结果表明，ATF7 和 TERRA 在父系压力诱导的后代端粒缩短中发挥关键作用。
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