NSD1 is essential for early post‐implantation development and has a catalytically active SET domain

The nuclear receptor‐binding SET domain‐containing protein (NSD1) belongs to an emerging family of proteins, which have all been implicated in human malignancy. To gain insight into the biological functions of NSD1, we have generated NSD1‐deficient mice by gene disruption. Homozygous mutant NSD1 embryos, which initiate mesoderm formation, display a high incidence of apoptosis and fail to complete gastrulation, indicating that NSD1 is a developmental regulatory protein that exerts function(s) essential for early post‐implantation development. We have also examined the enzymatic potential of NSD1 and found that its SET domain possesses intrinsic histone methyltransferase activity with specificity for Lys36 of histone H3 (H3‐K36) and Lys20 of histone H4 (H4‐K20).

[1]  黒滝 直弘.  私の論文から Haploinsufficiency of NSD1 causes Sotos syndrome , 2003 .

[2]  M. Mattéi,et al.  Isolation and Characterization ofSuv39h2, a Second Histone H3 Methyltransferase Gene That Displays Testis-Specific Expression , 2000, Molecular and Cellular Biology.

[3]  Karl Mechtler,et al.  Loss of the Suv39h Histone Methyltransferases Impairs Mammalian Heterochromatin and Genome Stability , 2001, Cell.

[4]  D. Robyr,et al.  Nuclear hormone receptor coregulators in action: diversity for shared tasks. , 2000, Molecular endocrinology.

[5]  D. Reinberg,et al.  Set9, a novel histone H3 methyltransferase that facilitates transcription by precluding histone tail modifications required for heterochromatin formation. , 2002, Genes & development.

[6]  C. Ponting,et al.  Regulation of chromatin structure by site-specific histone H3 methyltransferases , 2000, Nature.

[7]  J. Vonesch,et al.  Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators , 1998, The EMBO journal.

[8]  P. Chambon,et al.  In vivo functional analysis of the Hoxa-1 3' retinoic acid response element (3'RARE). , 1997, Development.

[9]  T. Kouzarides.  Histone methylation in transcriptional control. , 2002, Current opinion in genetics & development.

[10]  Paul Tempst,et al.  PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. , 2002, Molecular cell.

[11]  J. D. den Dunnen,et al.  The PWWP domain: a potential protein–protein interaction domain in nuclear proteins influencing differentiation? , 2000, FEBS letters.

[12]  A. Moorman,et al.  WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma. , 1998, Human molecular genetics.

[13]  P. Grant,et al.  Set2 Is a Nucleosomal Histone H3-Selective Methyltransferase That Mediates Transcriptional Repression , 2002, Molecular and Cellular Biology.

[14]  J. Workman,et al.  Analysis of transcription factor-mediated remodeling of nucleosomal arrays in a purified system. , 1997, Methods.

[15]  Hengbin Wang,et al.  Purification and functional characterization of a histone H3-lysine 4-specific methyltransferase. , 2001, Molecular cell.

[16]  Andrew P. McMahon,et al.  Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity , 1993, Cell.

[17]  P. Chambon,et al.  NSD3, a new SET domain-containing gene, maps to 8p12 and is amplified in human breast cancer cell lines. , 2001, Genomics.

[18]  P. Murphy,et al.  Expression of the mouse labial-like homeobox-containing genes, Hox 2.9 and Hox 1.6, during segmentation of the hindbrain. , 1991, Development.

[19]  J. Cheng,et al.  A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. , 2001, Blood.

[20]  Christian Beisel,et al.  Histone methylation by the Drosophila epigenetic transcriptional regulator Ash1 , 2002, Nature.

[21]  T. Gibson,et al.  The PHD finger: implications for chromatin-mediated transcriptional regulation. , 1995, Trends in biochemical sciences.

[22]  P. L. Bergsagel,et al.  The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. , 1998, Blood.

[23]  A. Veronese,et al.  NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). , 2002, Blood.

[24]  B. Herrmann,et al.  Immunohistochemical analysis of the Brachyury protein in wild-type and mutant mouse embryos. , 1994, Developmental biology.

[25]  Andrew J. Bannister,et al.  Unsafe SETs: histone lysine methyltransferases and cancer. , 2002, Trends in biochemical sciences.

[26]  T. Jenuwein.  Re-SET-ting heterochromatin by histone methyltransferases. , 2001, Trends in cell biology.

[27]  R. Marmorstein.  Structure of SET domain proteins: a new twist on histone methylation. , 2003, Trends in biochemical sciences.

[28]  P. Chambon,et al.  Looking at nuclear receptors from the heights of Erice , 2002, EMBO reports.

[29]  G. Reuter,et al.  The protein encoded by the Drosophila position‐effect variegation suppressor gene Su(var)3‐9 combines domains of antagonistic regulators of homeotic gene complexes. , 1994, The EMBO journal.

[30]  R. Behringer,et al.  Mouse gastrulation: the formation of a mammalian body plan , 1997, Mechanisms of Development.

[31]  Stuart L. Schreiber,et al.  Active genes are tri-methylated at K4 of histone H3 , 2002, Nature.

[32]  Yi Zhang,et al.  Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor , 2002, Oncogene.

[33]  Hengbin Wang,et al.  Purification and Functional Characterization of SET8, a Nucleosomal Histone H4-Lysine 20-Specific Methyltransferase , 2002, Current Biology.

[34]  A. Bolcato-Bellemin,et al.  Dorso-ventral and rostro-caudal sequential expression of M-twist in the postimplantation murine embryo , 1995, Mechanisms of Development.

[35]  H. Kato,et al.  G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. , 2002, Genes & development.

[36]  M. Surani,et al.  The Polycomb-Group GeneEzh2 Is Required for Early Mouse Development , 2001, Molecular and Cellular Biology.

[37]  Christoph H Borchers,et al.  Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast. , 2003, Genes & development.

[38]  G. Blobel,et al.  The peptide repeat domain of nucleoporin Nup98 functions as a docking site in transport across the nuclear pore complex , 1995, Cell.

[39]  S. Korsmeyer,et al.  Altered Hox expression and segmental identity in Mll-mutant mice , 1995, Nature.

[40]  C. Glass,et al.  Coregulator Codes of Transcriptional Regulation by Nuclear Receptors* , 2001, The Journal of Biological Chemistry.

[41]  Y. Fukushima,et al.  Haploinsufficiency of NSD1 causes Sotos syndrome , 2002, Nature Genetics.