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A poised chromatin platform for TGF-β access to master regulators

Qiaoran Xi1, Zhanxin Wang, Alexia-Ileana Zaromytidou

  • 1Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Cell
|December 27, 2011
PubMed

Insights

Nodal signals activate embryonic stem cell differentiation by targeting the poised histone mark H3K9me3. This interaction recruits key proteins, enabling the activation of master regulators for cell fate decisions.

Area of Science:

  • Epigenetics
  • Stem Cell Biology
  • Molecular Signaling

Background:

  • Master regulators of differentiation are silenced by specific chromatin marks, remaining poised for activation.
  • Extracellular signals, such as nodal TGF-β, can trigger the transition from a poised to an active state.

Purpose of the Study:

  • To elucidate the mechanism by which nodal TGF-β signals trigger differentiation in mammalian embryonic stem cells.
  • To investigate the role of specific histone marks and protein complexes in activating differentiation regulators.

Main Methods:

  • Analysis of protein-DNA interactions using crystal structures.
  • Investigated the binding of TRIM33-Smad2/3 complexes to histone peptides.
  • Studied the displacement of HP1γ and recruitment of Pol II.

Main Results:

  • Nodal signals utilize the poised histone mark H3K9me3 to initiate stem cell differentiation.
  • The TRIM33 PHD-Bromo cassette binds to H3K9me3 and H3K18ac, facilitating access to differentiation regulators.
  • This interaction displaces HP1γ, allowing Smad4-Smad2/3 recruitment and Pol II activation, with Smad4 enhancing H3K18 acetylation.

Conclusions:

  • Nodal signaling employs H3K9me3 as a platform to activate poised master regulators of stem cell differentiation.
  • The interplay between histone modifications and protein complexes is crucial for dynamic changes in chromatin accessibility and gene activation during differentiation.

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