Structural insights into trans-histone regulation of H3K4 methylation by unique histone H4 binding of MLL3/4.,Nature Communications

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Structural insights into trans-histone regulation of H3K4 methylation by unique histone H4 binding of MLL3/4.
Nature Communications ( IF 14.7 ) Pub Date : 2019-01-03 , DOI: 10.1038/s41467-018-07906-3
Yanli Liu ₁ , Su Qin ₁ , Tsai-Yu Chen ₂ , Ming Lei ₁ , Shilpa S Dhar ₂ , Jolene Caifeng Ho ₁ , Aiping Dong ₁ , Peter Loppnau ₁ , Yanjun Li ₁ , Min Gyu Lee ₂ , Jinrong Min _{1,

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Affiliation

MLL3 and MLL4 are two closely related members of the SET1/MLL family of histone H3K4 methyltransferases and are responsible for monomethylating histone H3K4 on enhancers, which are essential in regulating cell-type-specific gene expression. Mutations of MLL3 or MLL4 have been reported in different types of cancer. Recently, the PHD domains of MLL3/4 have been reported to recruit the MLL3/4 complexes to their target genes by binding to histone H4 during the NT2/D1 stem cell differentiation. Here we show that an extended PHD domain (ePHD6) involving the sixth PHD domain and its preceding zinc finger in MLL3 and MLL4 specifically recognizes an H4H18-containing histone H4 fragment and that modifications of residues surrounding H4H18 modulate H4 binding to MLL3/4. Our in vitro methyltransferase assays and cellular experiments further reveal that the interaction between ePHD6 of MLL3/4 and histone H4 is required for their nucleosomal methylation activity and MLL4-mediated neuronal differentiation of NT2/D1 cells.

中文翻译：

通过独特的组蛋白H4与MLL3 / 4结合，对H3K4甲基化进行反组蛋白调节的结构见解。

MLL3和MLL4是组蛋白H3K4甲基转移酶SET1 / MLL家族的两个密切相关的成员，负责增强子上组蛋白H3K4的单甲基化，这在调节细胞类型特异性基因表达中至关重要。已经报道了在不同类型的癌症中MLL3或MLL4的突变。最近，据报道，在NT2 / D1干细胞分化过程中，通过与组蛋白H4结合，MLL3 / 4的PHD结构域将MLL3 / 4复合物募集到其靶基因上。在这里，我们显示一个扩展的PHD结构域（ePHD6），涉及第六个PHD结构域及其在MLL3和MLL4中的先前的锌指，特异性识别包含H4H18的组蛋白H4片段，修饰围绕H4H18的残基可调节H4与MLL3 / 4的结合。

更新日期：2019-01-03

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