Kalakonda N, Fischle W, Boccuni P, Gurvich N, Hoya-Arias R, Zhao X, Miyata Y, Macgrogan D, Zhang J, Sims J K, Rice J C, Nimer S D
Laboratory of Molecular Aspects of Hematopoiesis, Sloan-Kettering Institute, New York, NY, USA.
Oncogene. 2008 Jul 17;27(31):4293-304. doi: 10.1038/onc.2008.67. Epub 2008 Apr 14.
Lethal 3 malignant brain tumor 1 (L3MBTL1), a homolog of the Drosophila polycomb tumor suppressor l(3)mbt, contains three tandem MBT repeats (3xMBT) that are critical for transcriptional repression. We recently reported that the 3xMBT repeats interact with mono- and dimethylated lysines in the amino termini of histones H4 and H1b to promote methylation-dependent chromatin compaction. Using a series of histone peptides, we now show that the recognition of mono- and dimethylated lysines in histones H3, H4 and H1.4 (but not their trimethylated or unmodified counterparts) by 3xMBT occurs in the context of a basic environment, requiring a conserved aspartic acid (D355) in the second MBT repeat. Despite the broad range of in vitro binding, the chromatin association of L3MBTL1 mirrors the progressive accumulation of H4K20 monomethylation during the cell cycle. Furthermore, transcriptional repression by L3MBTL1 is enhanced by the H4K20 monomethyltransferase PR-SET7 (to which it binds) but not SUV420H1 (an H4K20 trimethylase) or G9a (an H3K9 dimethylase) and knockdown of PR-SET7 decreases H4K20me1 levels and the chromatin association of L3MBTL1. Our studies identify the importance of H4K20 monomethylation and of PR-SET7 for L3MBTL1 function.
致死性3型恶性脑肿瘤1（L3MBTL1）是果蝇多梳肿瘤抑制因子l(3)mbt的同源物，包含三个串联的MBT重复序列（3xMBT），这些序列对转录抑制至关重要。我们最近报道，3xMBT重复序列与组蛋白H4和H1b氨基末端的单甲基化和二甲基化赖氨酸相互作用，以促进甲基化依赖的染色质压缩。使用一系列组蛋白肽，我们现在表明，3xMBT对组蛋白H3、H4和H1.4中的单甲基化和二甲基化赖氨酸（而非其三甲基化或未修饰的对应物）的识别发生在碱性环境中，需要第二个MBT重复序列中一个保守的天冬氨酸（D355）。尽管体外结合范围广泛，但L3MBTL1与染色质的结合反映了细胞周期中H4K20单甲基化的逐步积累。此外，L3MBTL1的转录抑制作用通过与其结合的H4K20单甲基转移酶PR-SET7增强，但不通过SUV420H1（一种H4K20三甲基化酶）或G9a（一种H3K9二甲基化酶）增强，并且敲低PR-SET7会降低H4K20me1水平和L3MBTL1与染色质的结合。我们的研究确定了H4K20单甲基化和PR-SET7对L3MBTL1功能的重要性。
