Myc Regulates Chromatin Decompaction and Nuclear Architecture During B Cell Activation

Mol Cell. 2017 Aug 17;67(4):566-578.e10. doi: 10.1016/j.molcel.2017.07.013. Epub 2017 Aug 10.

Abstract

50 years ago, Vincent Allfrey and colleagues discovered that lymphocyte activation triggers massive acetylation of chromatin. However, the molecular mechanisms driving epigenetic accessibility are still unknown. We here show that stimulated lymphocytes decondense chromatin by three differentially regulated steps. First, chromatin is repositioned away from the nuclear periphery in response to global acetylation. Second, histone nanodomain clusters decompact into mononucleosome fibers through a mechanism that requires Myc and continual energy input. Single-molecule imaging shows that this step lowers transcription factor residence time and non-specific collisions during sampling for DNA targets. Third, chromatin interactions shift from long range to predominantly short range, and CTCF-mediated loops and contact domains double in numbers. This architectural change facilitates cognate promoter-enhancer contacts and also requires Myc and continual ATP production. Our results thus define the nature and transcriptional impact of chromatin decondensation and reveal an unexpected role for Myc in the establishment of nuclear topology in mammalian cells.

Keywords: B cells; CTCF; Histone acetylation; chromatin remodeling; cohesin; immune response; myc; nanoscopy; nuclear architecture; transcriptome amplification.

MeSH terms

  • Acetyl Coenzyme A / metabolism
  • Acetylation
  • Adenosine Triphosphate / metabolism
  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Cell Cycle*
  • Cell Line
  • Cell Nucleus / metabolism*
  • Chromatin / chemistry
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Chromatin Assembly and Disassembly*
  • DNA Methylation
  • Epigenesis, Genetic
  • Genotype
  • Histones / chemistry
  • Histones / metabolism*
  • Immunity, Humoral
  • Lymphocyte Activation*
  • Methylation
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nucleic Acid Conformation
  • Phenotype
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-myc / chemistry
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Single Molecule Imaging
  • Structure-Activity Relationship
  • Time Factors
  • Transcription, Genetic

Substances

  • Chromatin
  • Histones
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Acetyl Coenzyme A
  • Adenosine Triphosphate