The Cross-Regulation Between Set1, Clr4, and Lsd1/2 in Schizosaccharomyces pombe.
The Cross-Regulation Between Set1, Clr4, and Lsd1/2 in Schizosaccharomyces pombe.
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DOI：
10.1371/journal.pgen.1011107
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发表时间：
2024-01
期刊：
影响因子：
4.5
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中科院分区：
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--
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真核染色质被组织成沉默的异染色质或松弛的常染色质区域，其控制转录机器的可及性，从而调节基因表达。在裂殖酵母裂殖酵母中，Set 1是唯一的H3 K4甲基转移酶，并且主要富集在活跃转录基因的启动子处。相比之下，Clr 4甲基转移酶启动H3 K9甲基化，这长期以来被认为是异染色质沉默的标志。Lsd 1和Lsd 2是两种高度保守的H3 K4和H3 K9脱甲基酶。由于这些组蛋白修饰酶在维持组蛋白甲基化模式和基因表达谱中起关键作用，因此这些酶之间的交叉调节是复杂调控网络的一部分。因此，阐明控制它们的信号和相互调节的机制仍然至关重要。在这里，我们证明了C端截短突变体lsd 1-ΔHMG和lsd 2-ΔC不会损害Lsd 1/2复合物的完整性，但会损害它们在靶基因组位点启动子区的染色质结合能力。我们确定了Lsd 1/2和Raf 2或Swd 2之间的蛋白质-蛋白质相互作用，它们分别是Clr 4复合物（CLRC）和Set 1相关复合物（COMPASS）的亚基。我们发现Clr 4和Set 1通过泛素-蛋白酶体依赖性途径以相反的方式调节Lsd 1和Lsd 2的蛋白水平。在热应激期间，Lsd 1和Lsd 2的蛋白水平以Set 1依赖性方式上调。蛋白质水平的增加对于胁迫条件下的差异基因表达至关重要。总之，我们的研究结果支持了一个交叉调节模型，通过该模型，Set 1和Clr 4甲基转移酶控制Lsd 1/2去甲基化酶的蛋白水平，以塑造动态染色质景观。组蛋白修饰酶对组蛋白进行共价修饰。这些修饰就像化学标签一样，可以收紧或放松DNA结构，影响基因的开启或关闭。在裂变酵母中，Set 1甲基化组蛋白H3赖氨酸4，其标记松散包装的DNA并与基因激活相关;而Clr 4甲基化组蛋白H3赖氨酸9，其代表紧密包装的DNA的标志并与基因沉默相关。在这里，我们显示了这两种酶之间的调节关系，并与两个赖氨酸特异性脱甲基酶（Lsd 1/2），它可以删除由Clr 4和Set 1添加的甲基标签。Clr 4和Set 1对Lsd 1和Lsd 2蛋白水平具有相反的影响。Clr 4降低Lsd 1/2的水平，而Set 1促进其稳定性。这种对Lsd 1/2水平的控制是通过泛素-蛋白酶体依赖性途径实现的。通过研究这些相互作用，我们发现了一种新的调节机制，帮助裂变酵母维持这些活性/抑制性组蛋白修饰酶的平衡水平。了解这些复杂的调控网络为基因控制提供了重要的见解，并增强了我们对细胞内复杂相互作用的理解。
Eukaryotic chromatin is organized into either silenced heterochromatin or relaxed euchromatin regions, which controls the accessibility of transcriptional machinery and thus regulates gene expression. In fission yeast, Schizosaccharomyces pombe, Set1 is the sole H3K4 methyltransferase and is mainly enriched at the promoters of actively transcribed genes. In contrast, Clr4 methyltransferase initiates H3K9 methylation, which has long been regarded as a hallmark of heterochromatic silencing. Lsd1 and Lsd2 are two highly conserved H3K4 and H3K9 demethylases. As these histone-modifying enzymes perform critical roles in maintaining histone methylation patterns and, consequently, gene expression profiles, cross-regulations among these enzymes are part of the complex regulatory networks. Thus, elucidating the mechanisms that govern their signaling and mutual regulations remains crucial. Here, we demonstrated that C-terminal truncation mutants, lsd1-ΔHMG and lsd2-ΔC, do not compromise the integrity of the Lsd1/2 complex but impair their chromatin-binding capacity at the promoter region of target genomic loci. We identified protein-protein interactions between Lsd1/2 and Raf2 or Swd2, which are the subunits of the Clr4 complex (CLRC) and Set1-associated complex (COMPASS), respectively. We showed that Clr4 and Set1 modulate the protein levels of Lsd1 and Lsd2 in opposite ways through the ubiquitin-proteasome-dependent pathway. During heat stress, the protein levels of Lsd1 and Lsd2 are upregulated in a Set1-dependent manner. The increase in protein levels is crucial for differential gene expression under stress conditions. Together, our results support a cross-regulatory model by which Set1 and Clr4 methyltransferases control the protein levels of Lsd1/2 demethylases to shape the dynamic chromatin landscape. Histone-modifying enzymes make covalent modifications to histones. These modifications act like chemical tags that can either tighten or loosen the DNA structure, affecting whether genes are turned on or off. In fission yeast, Set1 methylates histone H3 lysine 4, which marks loosely packed DNA and is associated with gene activation; while Clr4 methylates histone H3 lysine 9, which represents a hallmark of the tightly packed DNA and is associated with gene silencing. Here, we show a regulatory relationship between these two enzymes and with two lysine-specific demethylases (Lsd1/2), which can remove the methyl tags added by Clr4 and Set1. Clr4 and Set1 have opposite effects on Lsd1 and Lsd2 protein levels. Clr4 reduces the levels of Lsd1/2, while Set1 promotes their stability. This control over the levels of Lsd1/2 is achieved through the ubiquitin-proteasome-dependent pathway. By studying these interactions, we have uncovered a novel regulatory mechanism that helps fission yeast maintain a balanced level of these active/repressive histone-modifying enzymes. Understanding these intricate regulatory networks offers important insights into gene control and enhances our comprehension of the complex interactions within cells.
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影响因子：
4.5
作者：
Buscaino A;White SA;Houston DR;Lejeune E;Simmer F;de Lima Alves F;Diyora PT;Urano T;Bayne EH;Rappsilber J;Allshire RC
通讯作者：
Allshire RC
影响因子：
--
作者：
Collins, Sean R.;Roguev, Assen;Krogan, Nevan J.
通讯作者：
Krogan, Nevan J.
DOI：
10.1007/bf00433721
发表时间：
1968-01-01
期刊：
MOLECULAR AND GENERAL GENETICS
影响因子：
--
作者：
BRESCH, C;MULLER, G;EGEL, R
通讯作者：
EGEL, R
影响因子：
64.5
作者：
Braun S;Garcia JF;Rowley M;Rougemaille M;Shankar S;Madhani HD
通讯作者：
Madhani HD
影响因子：
3.4
作者：
Basisty N;Meyer JG;Schilling B
通讯作者：
Schilling B