Functional Genomics and Medicine

Research

Functional analysis of a novel BTB domain-containing zinc finger protein CIBZ (Assist.Prof. Matsuda)

DNA methylation is an epigenetic modification of the genome that plays critical roles in the regulation of cell proliferation, differentiation, apoptosis and tumorigenesis. In mammals, DNA methylation patterns are established and maintained by the DNA methyltransferases, Dnmt3a/3b and Dnmt1, respectively. The methylated DNA binding proteins (MBPs) bind the methylated sites and repress transcription of the corresponding genes. Evidence from knockout mice show that DNA methyltransferases are essential for the mouse embryogenesis, suggesting that MBPs are also important in the regulation of this process. In contrast, results of the known MBPs knockout mice show that they don’t play critical roles during the embryonic development, implicating the existence of new MBP(s).

We identified CIBZ (ZBTB38 in human), a murine BTB-containing zinc finger protein that can directly bind to methylated DNA. We demonstrate that CIBZ regulates apoptosis and myogenesis in murine cells, and regulates embryonic stem (ES) cells proliferation via Nanog. Subsequently, we demonstrated that CIBZ functions as a gatekeeper of ES cell pluripotency in undifferentiated ES Cells, and CIBZ regulates cardiac lineage differentiation.

Currently, (1) We generated the conditional CIBZ knockout (flox-neo/+) mice using Cre/loxP system. Studies were undertaken to explore its functions, especially on embryogenesis, cardiac and myoblast development in mice. (2) We want to explore chemicals that antagonize CIBZ has impact on improving the efficiency of myoblast differentiation in muscular dystrophy model mice, and cardiomyocytes regeneration in varies cardiomyopathy model mice.

References

  1. 哺乳類の発生や分化におけるメチル化DNA結合タンパク質の役割
    松田永照、西尾美紀、石田靖雅
    Bio Clinica 31巻５号、p79-84, 2016
  2. CtBP-interacting BTB zinc finger protein (CIBZ) promotes proliferation and G1/S transition in embryonic stem cells via Nanog
    Tomonori Nishii, Yu Oikawa, Eishou Matsuda et al.
    J. Biol. Chem. 287:12417-24, 2012
  3. The methyl-CpG-binding protein CIBZ suppresses myogenic differentiation by directly inhibiting myogenin expression
    Yu Oikawa, Reiko Omori, Eishou Matsuda et al.
    Cell Research. 21:1578-90, 2011
  4. Down-regulation of CIBZ, a novel substrate of caspase-3, induces apoptosis
    Yu Oikawa, Masashi Kawaichi, Eishou Matsuda et al.
    J. Biol. Chem. 283:14242-47, 2008
  5. Identification of a novel BTB-zinc finger transcriptional repressor, CIBZ, that interacts with CtBP corepressor
    Nobuhiro Sasai, Masashi Kawaichi, Eishou Matsuda et al.
    Genes to Cells. 10(9):871-85, 2005
  6. Expression profiling with arrays of randomly disrupted genes in mouse embryonic stem cells leads to in vivo functional analysis
    Eishou Matsuda, Toshiaki Shigeoka, Yasumasa Ishida et al.
    Proc. Natl. Acad. Sci. USA 101:4170-4174, 2004

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