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The Trithorax group protein Lid is a trimethyl histone H3K4 demethylase required for dMyc-induced cell growth

Julie Secombe1, Ling Li, Leni Carlos

  • 1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.

Genes & Development
|February 22, 2007
PubMed

Insights

Researchers identified Little imaginal discs (Lid) as a regulator of Myc-induced cell growth. Lid, a histone demethylase, interacts with Myc to influence gene expression and chromatin states.

Area of Science:

  • Molecular Biology
  • Genetics
  • Epigenetics

Background:

  • The Myc oncoprotein drives cell growth and proliferation, but its transcriptional specificity is not fully understood.
  • Identifying regulators of Myc's function is crucial for understanding cell growth control.

Purpose of the Study:

  • To identify novel regulators of Myc's transcriptional specificity and function.
  • To elucidate the molecular mechanism by which Myc controls cell growth.

Main Methods:

  • Genetic screening in Drosophila to identify regulators of dMyc.
  • Biochemical assays to study protein-protein interactions (Lid and dMyc/c-Myc).
  • In vivo enzymatic assays to determine Lid's histone demethylase activity and its regulation by Myc.

Main Results:

  • The Trithorax group protein Little imaginal discs (Lid) was identified as a regulator of dMyc-induced cell growth.
  • Lid binds to dMyc and is essential for the expression of the growth gene Nop60B.
  • Mammalian Lid orthologs (Rbp-2/JARID1A, Plu-1/JARID1B) also bind c-Myc, indicating conserved function.
  • Lid functions as a JmjC-dependent trimethyl H3K4 demethylase in vivo.
  • Myc binding negatively regulates Lid's demethylase activity by binding to its JmjC domain.
  • Myc binding correlates with high trimethylated H3K4 levels, suggesting the Lid-Myc complex maintains this chromatin state.

Conclusions:

  • The Lid-Myc interaction is conserved across species and plays a key role in regulating Myc's function.
  • Myc binding to Lid inhibits its H3K4 demethylase activity, potentially facilitating Myc's association with specific chromatin regions.
  • This mechanism provides insight into the molecular determinants of Myc's transcriptional specificity and its role in cell growth regulation.

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