WDR5 in porcine preimplantation embryos: expression, regulation of epigenetic modifications and requirement for early development
WDR5 in porcine preimplantation embryos: expression, regulation of epigenetic modifications and requirement for early development
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猪植入前胚胎中的 WDR5：表达、表观遗传修饰的调控以及早期发育的要求
DOI：
10.1093/biolre/iox020
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发表时间：
2017-04-01
影响因子：
3.6
通讯作者：
Zhang, Yunhai
中科院分区：
文献类型：
--
作者：
Ding, Biao;Cao, Zubing;Zhang, Yunhai
摘要WD含重复序列蛋白5（WD repeat-containing protein 5，WDR 5）是保守的WD 40蛋白家族成员，是混合系白血病（MLL）复合体的重要组成部分，在组蛋白H3赖氨酸4（H3 K4）甲基化、胚胎干细胞自我更新、诱导多能干细胞形成等重要生物学过程中起着重要作用。然而，WDR 5在猪植入前胚胎发育过程中的表达模式和功能作用仍不清楚。结果表明，WDR 5基因在猪早期胚胎中的表达具有阶段特异性。此外，通过RNAi介导的WDR 5沉默或WDR 5的药理学抑制降低囊胚率和每个囊胚的总细胞数。敲除WDR 5还干扰了几个多能性基因的表达。有趣的是，H3 K4的三甲基化（H3 K4 me 3）水平通过WDR 5耗尽而显著增加。进一步的分析显示，MLL 3的缺失表型模仿了WDR 5敲低，触发了H3 K4 me 3水平的增加。同时，WDR 5缺失显著降低组蛋白H4赖氨酸16乙酰化（H4 K16 ac）水平及其第一个缺失的书写者雄性（MOF）。最后但并非最不重要的是，WDR 5敲低诱导猪植入前发育过程中的DNA损伤和DNA修复缺陷。综上所述，所述研究的结果证实，WDR 5可能通过调节关键的表观遗传修饰和基因组完整性在猪植入前胚胎中起重要作用。WDR 5参与调控猪胚胎发育，可能通过调控表观遗传修饰（H3 K4 me 3和H4 K16 ac）和基因组完整性介导。
Abstract WD repeat-containing protein 5 (WDR5), a member of conserved WD40 protein family, is an essential component of the mixed lineage leukemia (MLL) complexes, which are crucial for numerous key biological processes including methylation of histone H3 lysine 4 (H3K4), self-renewal of embryonic stem cells, and formation of induced pluripotent stem cells. The expression pattern and functional role of WDR5 during porcine preimplantation embryonic development, however, remain unknown. Our results showed that the transcripts and protein of WDR5 exhibited stage-specific expression pattern in porcine early embryos. Moreover, blastocyst rate and total cell number per blastocyst were reduced by RNAi-mediated silencing of WDR5 or pharmacological inhibition of WDR5. Knockdown of WDR5 also disturbed the expression of several pluripotency genes. Interestingly, tri-methylation of H3K4 (H3K4me3) level was dramatically increased by WDR5 depletion. Further analysis revealed that loss of MLL3 phenocopied WDR5 knockdown, triggering increased H3K4me3 level. Simultaneously, WDR5 depletion significantly decreased the levels of histone H4 lysine 16 acetylation (H4K16ac) and its writer males absent on the first (MOF). Last but not least, WDR5 knockdown induced DNA damage and DNA repair defects during porcine preimplantation development. Taken together, results of described studies establish that WDR5 plays a significant role in porcine preimplantation embryos probably through regulating key epigenetic modifications and genome integrity. Summary Sentence WDR5 participates in the regulation of porcine embryonic development, likely mediated by regulation of epigenetic modifications (H3K4me3 and H4K16ac) and genome integrity.