Paternal poly (ADP-ribose) metabolism modulates retention of inheritable sperm histones and early embryonic gene expression.
Paternal poly (ADP-ribose) metabolism modulates retention of inheritable sperm histones and early embryonic gene expression.
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DOI：
10.1371/journal.pgen.1004317
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发表时间：
2014-05
期刊：
影响因子：
4.5
通讯作者：
Meyer RG
中科院分区：
文献类型：
--
作者：
Ihara M;Meyer-Ficca ML;Leu NA;Rao S;Li F;Gregory BD;Zalenskaya IA;Schultz RM;Meyer RG
为了实现精子功能所需的极端核凝聚，在哺乳动物的精子发生过程中，大多数组蛋白都被鱼精蛋白取代。成熟精子只保留一小部分核小体，部分核小体富含基因调控序列，最近的发现表明，这些保留的组蛋白提供了表观遗传信息，调控受精后胚胎发育相关基因的子集的表达。我们提出了这一诱人的假说，通过分析两个由于精子发生过程中聚(ADP-核糖)(PAR)代谢受损而在成熟精子中显示组蛋白位置异常的小鼠模型，并使用基于MNase消化的单核糖体DNA浓缩方法在全基因组特定的基因位置确定了精子组蛋白保留的改变。然后，我们着手确定这些基因在用这些精子产生的胚胎中的表达发生了多大程度的变化。对于对照精子，大多数基因都显示出某种程度的组蛋白关联，这出人意料地表明，组蛋白在精子基因中的保留并不是一个要么全有要么全无的现象，少数组蛋白可能仍然与整个基因组中的基因相关。然而，当PAR代谢受损时，在许多基因座上保留的组蛋白的数量会发生变化。为了确定精子组蛋白结合与胚胎基因表达之间是否存在关联，我们利用基因芯片和RNA测序技术测定了来自这些精子的单个2-细胞胚胎的转录组。引人注目的是，在这些胚胎中差异表达的基因中，有一部分适度但在统计学上有意义，在他们父亲的精子中，相应的基因位点也显示出不同的组蛋白保留。这些发现为精子组蛋白保留和胚胎基因表达之间存在联系提供了新的证据。在精子发生过程中，并不是所有的组蛋白都被精蛋白取代，这一点已经知道了近30年，此外还有一个概念，即精蛋白不携带任何特定的表观遗传信息，而组蛋白通常带有具有表观遗传调节功能的翻译后修饰。最近，其他人在高分辨率下证明了在转录起始点周围具有明显表观遗传修饰的组蛋白以及未甲基化的GC丰富的启动子区域和外显子在小鼠和人类精子中的富集组蛋白。精子组蛋白保留的共同原理在进化上的保守性为核小体的表观遗传提供了合理的理论基础。本研究采用了一种不同的方法来检验最重要的假设，即精子组蛋白与早期胚胎基因表达有关，通过分析来自精子的2-细胞胚胎中基因的表达，其中这些基因的组蛋白关联被实验改变。结果与上述假设一致，并支持精子组蛋白是通过雄性生殖系进行表观遗传的潜在媒介的观点，这也可能导致哺乳动物在影响敏感的染色质调节途径(如PAR代谢)的环境或饮食因素的表型变异。
To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo. That not all histones are replaced by protamines in the sperm nucleus during spermiogenesis has been known for almost three decades, along with the notion that protamines do not bear any specific epigenetic information whereas histones typically carry posttranslational modifications with epigenetic regulatory functions. The enrichment of histones with distinct epigenetic modifications around transcriptional start sites, as well as unmethylated GC-rich promoter regions and exons in murine and human sperm, has recently been demonstrated by others at high resolution. The evolutionary conservation of the common principles underlying sperm histone retention provides a plausible rationale for epigenetic inheritance by nucleosomes. The present study takes a different approach towards testing the overarching hypothesis that sperm histones are linked to early embryonic gene expression by analyzing expression of genes in 2-cell embryos originating from sperm in which gene histone association of these genes was experimentally altered. The results are consistent with the aforementioned hypothesis and support the view of sperm histones as potential mediators of epigenetic inheritance through the male germ line, which could also contribute to phenotypic variation in mammals in response to environmental or dietary factors that affect sensitive chromatin-modulating pathways such as PAR metabolism.
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影响因子：
64.5
作者：
Carone BR;Fauquier L;Habib N;Shea JM;Hart CE;Li R;Bock C;Li C;Gu H;Zamore PD;Meissner A;Weng Z;Hofmann HA;Friedman N;Rando OJ
通讯作者：
Rando OJ
影响因子：
16.8
作者：
Brykczynska, Urszula;Hisano, Mizue;Peters, Antoine H. F. M.
通讯作者：
Peters, Antoine H. F. M.
影响因子：
5.8
作者：
Grant, Gregory R.;Farkas, Michael H.;Pierce, Eric A.
通讯作者：
Pierce, Eric A.
影响因子：
7.5
作者：
Kraus, W. Lee
通讯作者：
Kraus, W. Lee
影响因子：
3.6
作者：
BIANCHI, PG;MANICARDI, GC;SAKKAS, D
通讯作者：
SAKKAS, D