A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome
A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome
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DOI：
10.1038/nature08086
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发表时间：
2009-07-09
期刊：
影响因子：
64.8
通讯作者：
Kaneda, Yasufumi
中科院分区：
文献类型：
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作者：
Nimura, Keisuke;Ura, Kiyoe;Kaneda, Yasufumi
多种组蛋白修饰由各种特定蛋白质催化和识别，建立起转录信号的独特修饰模式(1,2)。特别是，组蛋白 H3 在赖氨酸 36 (H3K36me3) 处的三甲基化与活跃转录区域相关，并且已被提议为持续转录提供标志 (3,4)；然而，H3K36me3 在高等真核生物中的控制机制和功能尚不清楚。在此，我们展示了 H3K36me3 特异性组蛋白甲基转移酶 (HMTase) Wolf-Hirschhorn 综合征候选 1（WHSC1，也称为 NSD2 或 MMSET）与发育转录因子一起在转录调节中发挥作用，这些转录因子的缺陷与人类疾病 Wolf-Hirschhorn 综合征 (WHS) 重叠 (5,6)。我们发现小鼠 Whsc1，五个假定的 Set2 同源物 (2,7,8) 之一，通过与胚胎干细胞中的细胞类型特异性转录因子 Sall1、Sall4 和 Nanog 以及胚胎心脏中的 Nkx2-5 相关联，沿着常染色质控制 H3K36me3，调节其靶基因的表达。 Whsc1 缺陷小鼠表现出生长迟缓和各种类似 WHS 的中线缺陷，包括先天性心血管异常。 Nkx2-5 杂合突变体心脏中 Whsc1 单倍体充足性的影响增加，表明它们的功能联系。我们认为 WHSC1 与发育转录因子一起发挥作用，以防止可能导致各种病理生理学的不适当转录。
Diverse histone modifications are catalysed and recognized by various specific proteins, establishing unique modification patterns that act as transcription signals(1,2). In particular, histone H3 trimethylation at lysine 36 (H3K36me3) is associated with actively transcribed regions and has been proposed to provide landmarks for continuing transcription(3,4); however, the control mechanisms and functions of H3K36me3 in higher eukaryotes are unknown. Here we show that the H3K36me3-specific histone methyltransferase (HMTase) Wolf-Hirschhorn syndrome candidate 1 (WHSC1, also known as NSD2 or MMSET) functions in transcriptional regulation together with developmental transcription factors whose defects overlap with the human disease Wolf Hirschhorn syndrome (WHS)(5,6). We found that mouse Whsc1, one of five putative Set2 homologues(2,7,8), governed H3K36me3 along euchromatin by associating with the cell-type-specific transcription factors Sall1, Sall4 and Nanog in embryonic stem cells, and Nkx2-5 in embryonic hearts, regulating the expression of their target genes. Whsc1-deficient mice showed growth retardation and various WHS-like midline defects, including congenital cardiovascular anomalies. The effects of Whsc1 haploin sufficiency were increased in Nkx2-5 heterozygous mutant hearts, indicating their functional link. We propose that WHSC1 functions together with developmental transcription factors to prevent the inappropriate transcription that can lead to various pathophysiologies.