Gene silencing quantitatively controls the function of a developmental trans-activator

Mol Cell. 2002 Jul;10(1):81-91. doi: 10.1016/s1097-2765(02)00564-6.


How a single cell gives rise to progeny with differing fates remains poorly understood. We examined cells lacking methyl CpG binding domain protein-2 (MBD2), a molecule that has been proposed to link DNA methylation to silent chromatin. Helper T cells from Mbd2(-/-) mice exhibit disordered differentiation. IL-4, the signature of a restricted set of progeny, is expressed ectopically in Mbd2(-/-) parent and daughter cells. Loss of MBD2-mediated silencing renders the normally essential activator, Gata-3, dispensable for IL-4 induction. Gata-3 and MBD2 act in competition, wherein each factor independently, and quantitatively, regulates the binary choice of whether heritable IL-4 expression is established. Gata-3 functions, in part, to displace MBD2 from methylated DNA. These results suggest that activating and silencing signals integrate to provide spatially and temporally restricted patterns of gene activity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding, Competitive
  • Cell Differentiation
  • Cell Line
  • Cell Lineage
  • Chromatin / metabolism
  • CpG Islands / genetics
  • DNA Methylation
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Flow Cytometry
  • GATA3 Transcription Factor
  • Gene Deletion
  • Gene Expression Regulation, Developmental*
  • Gene Silencing*
  • Interleukin-4 / genetics
  • Interleukin-4 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / metabolism
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*


  • Chromatin
  • DNA-Binding Proteins
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • MBD2 protein
  • Trans-Activators
  • Interleukin-4