Investigating crosstalk between H3K27 acetylation and H3K4 trimethylation in CRISPR/dCas-based epigenome editing and gene activation.
Investigating crosstalk between H3K27 acetylation and H3K4 trimethylation in CRISPR/dCas-based epigenome editing and gene activation.
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DOI：
10.1038/s41598-021-95398-5
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发表时间：
2021-08-05
影响因子：
4.6
通讯作者：
Liang FS
中科院分区：
文献类型：
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作者：
Zhao W;Xu Y;Wang Y;Gao D;King J;Xu Y;Liang FS
表观基因组编辑方法使人们能够精确操纵表观遗传修饰，如组蛋白转录后修饰(PTM)，以揭示其生物学功能。虽然组蛋白PTM与某些基因表达状态相关，但其因果关系仍然难以捉摸。组蛋白H3赖氨酸27乙酰化(H3K27ac)和组蛋白H3赖氨酸4三甲基化(H3K4me3)均与活性基因相关，位于活性启动子和增强子或转录起始点附近。虽然已经报道了组蛋白赖氨酸乙酰化和H3K4me3之间的串扰，但在转录激活过程中特定的表观遗传标记之间的关系仍然很不清楚。在这里，利用簇状规则间隔短回文重复序列(CRISPR)/基于DCAS的表观基因组编辑方法，我们发现在启动子区域异位引入H3K27ac导致了H3K4me3在TSS周围的浓缩和转录激活，而H3K4me3安装在启动子上不能诱导H3K27ac增加，也不能激活基因表达。用抑制剂JQ1阻断BRD蛋白对H3K27ac的读取，可阻断H3K27ac诱导的H3K4me3安装和下游基因的激活。此外，我们发现BRD2，而不是BRD4，介导了H3K4me3的安装和H3K27ac写入时的基因激活。我们的研究揭示了H3K27ac和H3K4me3在基因激活过程中的关系，并证明了基于CRISPR/DCAS的表观基因组编辑方法在阐明表观遗传机制之间的串扰方面的应用。
Epigenome editing methods enable the precise manipulation of epigenetic modifications, such as histone posttranscriptional modifications (PTMs), for uncovering their biological functions. While histone PTMs have been correlated with certain gene expression status, the causalities remain elusive. Histone H3 Lysine 27 acetylation (H3K27ac) and histone H3 Lysine 4 trimethylation (H3K4me3) are both associated with active genes, and located at active promoters and enhancers or around transcriptional start sites (TSSs). Although crosstalk between histone lysine acetylation and H3K4me3 has been reported, relationships between specific epigenetic marks during transcriptional activation remain largely unclear. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/dCas-based epigenome editing methods, we discovered that the ectopic introduction of H3K27ac in the promoter region lead to H3K4me3 enrichment around TSS and transcriptional activation, while H3K4me3 installation at the promoter cannot induce H3K27ac increase and failed to activate gene expression. Blocking the reading of H3K27ac by BRD proteins using inhibitor JQ1 abolished H3K27ac-induced H3K4me3 installation and downstream gene activation. Furthermore, we uncovered that BRD2, not BRD4, mediated H3K4me3 installation and gene activation upon H3K27ac writing. Our studies revealed the relationships between H3K27ac and H3K4me3 in gene activation process and demonstrated the application of CRISPR/dCas-based epigenome editing methods in elucidating the crosstalk between epigenetic mechanisms.
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影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
6
作者：
Bochyńska A;Lüscher-Firzlaff J;Lüscher B
通讯作者：
Lüscher B
影响因子：
3.7
作者：
Handoko L;Kaczkowski B;Hon CC;Lizio M;Wakamori M;Matsuda T;Ito T;Jeyamohan P;Sato Y;Sakamoto K;Yokoyama S;Kimura H;Minoda A;Umehara T
通讯作者：
Umehara T
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
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