Abstract
Diverse histone modifications are catalysed and recognized by various specific proteins, establishing unique modification patterns that act as transcription signals1,2. In particular, histone H3 trimethylation at lysine 36 (H3K36me3) is associated with actively transcribed regions and has been proposed to provide landmarks for continuing transcription3,4; 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 homologues2,7,8, 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 haploinsufficiency 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.
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Acknowledgements
We thank T. Richmond, R. Nishinakamura, H. Kurumizaka and M. Shirai for providing reagents and mice; S. Khochbin, S. Hirose, J. Godde and J. Takeuchi for their critical reading of the manuscript; and H. Niwa, H. Hamada, M. Yamamoto, S. Ohishi, H. Nakagami and members of the GTS laboratory for discussion and support. This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) and the Naito Foundation, and by funds from Osaka University for female researchers.
Author Contributions Y.K. provided support and general guidance for this work. K.U. planned and organized the project. K.N. designed and performed experiments. H.S. performed histological analysis of hearts. R.J.S., M.I. and M.O. contributed mouse resources. K.U. wrote the paper with K.N. and Y.K.
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Nimura, K., Ura, K., Shiratori, H. et al. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf–Hirschhorn syndrome. Nature 460, 287–291 (2009). https://doi.org/10.1038/nature08086
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DOI: https://doi.org/10.1038/nature08086
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