《Cell》亮点：干细胞身世之谜

　　

生物通报道，来自埃默里大学生物系和耶鲁大学遗传学系的研究者在最新一期的Cells杂志上发表了他们在表观遗传学方面的新见解，文章标题为：A C. elegans LSD1 Demethylase Contributes to Germline Immortality by Reprogramming Epigenetic Memory。

 

文章的通讯作者是埃默里大学生物系的William G.Kelly教授，第一作者David J.Katz，他是William实验室的博士后，现任埃默里大学副教授。William教授的实验室主要以C.elegans为模型研究干细胞的“母亲”受精卵的发育情况，研究胚胎发生期干细胞的发育情况，和多能性的维持机制。

 

干细胞一直都是生命科学领域的香饽饽，谁都在研究它，可是却没有人知道干细胞究竟是如何从受精卵逐步发育成胚胎干细胞的呢？当中的各种分子机制和表观遗传学机制没人清楚。而William的实验室正是要解开胚胎干细胞的身世之谜。

 

博士后David说，我们的这篇文章解释了受精卵发育的机制，简单的说，受精卵首先要清除来自母体和父体的遗传程序信息才可能分化成一个全新的生命。生物学的一个经典难题是，一个卵细胞和一个精子如何蜕变成一个新生命？当精子遇上卵细胞时，受精卵首先要清除来自亲代的特殊程序信息（精子或卵细胞自身的遗传程序信息），然后再开始生长成为一个新的生命。也正是这个原因，子代与亲代的表观遗传信息发生了深刻的变化。

 

研究人员发现程序重排与一个特殊的组蛋白修饰作用有关，这个组蛋白修饰作用牵涉到H3K4me2 demethylase LSD1/KDM1。如果这个组蛋白修饰发生突变将导致清除作用（清楚亲代的表观遗传学信息）失效。正常的C.elegans繁殖下一代的时候组蛋白的修饰信息不会传递给下一代。而如果发生突变，组蛋白的修饰信息会一代代传下去，研究小组做了个实验，把spr-5突变（这一突变会导致不孕），同时再突变LSD/KDM1，结果发现子代变得越来越继承亲代的不孕性状。而如果再从外界引进LSD/KDM1又使得子代清除亲代的表观遗传修饰程序的功能得以恢复。

 

这些结果表明，H3K4是一个具有维持子代表观遗传学记忆的蛋白，而在正常情况下LSD/KDm1（一种酶）能清除这些记忆，使得子代按照新的表观遗传学信息发育。

 

研究小组下一步将在小鼠模型上验证这一结论。

（生物通 小茜）

生物通推荐原文检索：A C. elegans LSD1 Demethylase Contributes to Germline Immortality by Reprogramming Epigenetic Memory

【Summary】

Epigenetic information undergoes extensive reprogramming in the germline between generations. This reprogramming may be essential to establish a developmental ground state in the zygote. We show that mutants in spr-5, the Caenorhabditis elegans ortholog of the H3K4me2 demethylase LSD1/KDM1, exhibit progressive sterility over many generations. This sterility correlates with the misregulation of spermatogenesis-expressed genes and transgenerational accumulation of the histone modification dimethylation of histone H3 on lysine 4 (H3K4me2). This suggests that H3K4me2 can serve as a stable epigenetic memory, and that erasure of H3K4me2 by LSD/KDM1 in the germline prevents the inappropriate transmission of this epigenetic memory from one generation to the next. Thus, our results provide direct mechanistic insights into the processes that are required for epigenetic reprogramming between generations.

 

 

简介

William G. Kelly, Ph.D.
Biology

Molecular Analysis of Epigenetic Regulation in Germ Cells
We use the genetic model system C. elegans to study how the "mother of all stem cells", the germ line, is established during embryogenesis and maintained during development. We have identified an "epigenetic erasure" process that separates pluripotent germ cells from somatic cells in the early embryo, and are studying epigenetic mechanisms in the embryonic germline that guard the germ cells during early development and regulate genomic activation. We also study how chromatin-based silencing mechanisms are targeted to large genomic regions, particularly the X chromosome, in adult germ cells. We have discovered imprinted X inactivation in C. elegans, and are using this as a model to analyze how genetic imprinting is established in gametogenesis. We have also recently identified mechanisms that silence unpaired DNA during meiosis, and are investigating how such mechanisms contribute to genome stability.