H3.3 Nucleosome Assembly Mutants Display a Late-Onset Maternal Effect
H3.3 Nucleosome Assembly Mutants Display a Late-Onset Maternal Effect
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DOI：
10.1016/j.cub.2020.04.046
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发表时间：
2020-06-22
期刊：
影响因子：
9.2
通讯作者：
Horvitz, H. Robert
中科院分区：
文献类型：
--
作者：
Burkhart, Kirk B.;Sando, Steven R.;Horvitz, H. Robert
母体遗传的RNA和蛋白质控制着胚胎的大部分发育。这些母体信息在胚胎发育之外的影响在很大程度上还不清楚。在这里，我们报告说，母亲的贡献，组蛋白H3.3组装复合物可以防止晚发型的解剖，生理和行为异常的C。优雅的。我们发现缺乏hira-1（一种进化上保守的H3.3沉积因子）的突变体具有严重的多效性缺陷，主要表现在成年期。这些迟发性缺陷可以从母体得到挽救，并且可以在hira-1（-/-）后代中检测到母体来源的HIRA-1蛋白。线粒体压力可能有助于迟发性缺陷，因为hira-1突变体显示线粒体压力，并且线粒体压力的诱导导致至少一些hira-1迟发性异常。一项对模拟hira-1突变表型的突变体的筛选鉴定出PQN-80--一种HIRA复合物组分，在人类中称为UBN 1--和XNP-1--第二种H3.3分子伴侣，在人类中称为ATRX。pqn-80和xnp-1异常也被母体挽救。此外，缺乏组蛋白H3.3的突变体具有类似于hira-1、pqn-80和xnp-1突变体的缺陷的迟发性缺陷。这些数据表明，H3.3组装复合物提供了非DNA为基础的遗传信息，可以显着影响成人表型。我们推测，类似的母体效应可能解释了晚发性人类疾病（如阿尔茨海默病、帕金森病和2型糖尿病）遗传性缺失的原因。
Maternally inherited RNA and proteins control much of embryonic development. The effect of such maternal information beyond embryonic development is largely unclear. Here, we report that maternal contribution of histone H3.3 assembly complexes can prevent the expression of late-onset anatomical, physiologic, and behavioral abnormalities of C. elegans. We show that mutants lacking hira-1, an evolutionarily conserved H3.3-deposition factor, have severe pleiotropic defects that manifest predominantly at adulthood. These late-onset defects can be maternally rescued, and maternally derived HIRA-1 protein can be detected in hira-1(-/-) progeny. Mitochondrial stress likely contributes to the late-onset defects, given that hira-1 mutants display mitochondrial stress, and the induction of mitochondrial stress results in at least some of the hira-1 late-onset abnormalities. A screen for mutants that mimic the hira-1 mutant phenotype identified PQN-80-a HIRA complex component, known as UBN1 in humans-and XNP-1-a second H3.3 chaperone, known as ATRX in humans. pqn-80 and xnp-1 abnormalities are also maternally rescued. Furthermore, mutants lacking histone H3.3 have a late-onset defect similar to a defect of hira-1, pqn-80, and xnp-1 mutants. These data demonstrate that H3.3 assembly complexes provide non-DNA-based heritable information that can markedly influence adult phenotype. We speculate that similar maternal effects might explain the missing heritability of late-onset human diseases, such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes.