Acetylation-Specific Interference by Anti-Histone H3K9ac Intrabody Results in Precise Modulation of Gene Expression.
Acetylation-Specific Interference by Anti-Histone H3K9ac Intrabody Results in Precise Modulation of Gene Expression.
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DOI：
10.3390/ijms23168892
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发表时间：
2022-08-10
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
在组蛋白翻译后修饰(PTM)中，赖氨酸乙酰化在染色质修饰酶介导的基因表达的表观遗传调控中起着关键作用。由于它们在生理和病理上的活性，已经开发出几种化合物来抑制这些蛋白质的功能。然而，这些类别的蛋白质的多效性代表了表观遗传药物的一个弱点。理想情况下，新一代表观遗传药物应该以分子精确的方式靶向靶蛋白上的单个乙酰化赖氨酸。我们利用PTM定向的干扰，基于体内(scFv-58F)选择性地结合组蛋白H3(H3K9ac)的乙酰化赖氨酸9(H3K9ac)，以检验以下假设：靶向H3K9ac比抑制安装该PTM的相应HAT酶产生更特异的效果。在酵母scFv-58F中，与两种成熟的HAT抑制剂相比，scFv-58F以更特异的方式调节基因表达。这种PTM特异性干扰调节了核糖体生物发生和功能相关基因的表达。在哺乳动物细胞中，scFv-58F诱导依赖于H3K9ac的特定基因表达的排他性变化。这些结果表明，H3K9ac特异性体内是一类新的分子的创立者，直接靶向组蛋白PTM，逆转了从抑制编写者酶到作用于PTM的范式。
Among Histone post-translational modifications (PTMs), lysine acetylation plays a pivotal role in the epigenetic regulation of gene expression, mediated by chromatin modifying enzymes. Due to their activity in physiology and pathology, several chemical compounds have been developed to inhibit the function of these proteins. However, the pleiotropy of these classes of proteins represents a weakness of epigenetic drugs. Ideally, a new generation of epigenetic drugs should target with molecular precision individual acetylated lysines on the target protein. We exploit a PTM-directed interference, based on an intrabody (scFv-58F) that selectively binds acetylated lysine 9 of histone H3 (H3K9ac), to test the hypothesis that targeting H3K9ac yields more specific effects than inhibiting the corresponding HAT enzyme that installs that PTM. In yeast scFv-58F modulates, gene expression in a more specific way, compared to two well-established HAT inhibitors. This PTM-specific interference modulated expression of genes involved in ribosome biogenesis and function. In mammalian cells, the scFv-58F induces exclusive changes in the H3K9ac-dependent expression of specific genes. These results suggest the H3K9ac-specific intrabody as the founder of a new class of molecules to directly target histone PTMs, inverting the paradigm from inhibiting the writer enzyme to acting on the PTM.
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影响因子：
2.2
作者：
Visintin M;Meli GA;Cannistraci I;Cattaneo A
通讯作者：
Cattaneo A
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
20.1
作者：
Gillette TG;Hill JA
通讯作者：
Hill JA
影响因子：
8.8
作者：
Cai, Ling;McCormick, Mark A.;Tu, Benjamin P.
通讯作者：
Tu, Benjamin P.