Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination

Genome Res. 2010 Jan;20(1):36-44. doi: 10.1101/gr.092114.109. Epub 2009 Nov 19.

Abstract

Embryonic stem (ES) cells are under precise control of both intrinsic self-renewal gene regulatory network and extrinsic growth factor-triggered signaling cascades. How external signaling pathways connect to core self-renewal transcriptional circuits is largely unknown. To probe this, we chose BMP signaling, which is previously recognized as a master control for both self-renewal and lineage commitment of murine ES cells. Here, we mapped target gene promoter occupancy of SMAD1/5 and SMAD4 on a genome-wide scale and found that they associate with a large group of developmental regulators that are enriched for H3K27 trimethylation and H3K4 trimethylation bivalent marks and are repressed in the self-renewing state, whereas they are rapidly induced upon differentiation. Smad knockdown experiments further indicate that SMAD-mediated BMP signaling is largely required for differentiation-related processes rather than directly influencing self-renewal. Among the SMAD-associated genes, we further identified Dpysl2 (previously known as Crmp2) and the H3K27 demethylase Kdm6b (previously known as Jmjd3) as BMP4-modulated early neural differentiation regulators. Combined with computational analysis, our results suggest that SMAD-mediated BMP signaling balances self-renewal versus differentiation by modulating a set of developmental regulators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Differentiation*
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Chromosome Mapping*
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Genome
  • Mice
  • Molecular Sequence Data
  • Neurons / cytology
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic
  • Sequence Analysis, DNA
  • Signal Transduction*
  • Smad Proteins, Receptor-Regulated* / genetics
  • Smad Proteins, Receptor-Regulated* / metabolism
  • Smad1 Protein / genetics
  • Smad1 Protein / metabolism
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • Smad5 Protein / genetics
  • Smad5 Protein / metabolism

Substances

  • Bone Morphogenetic Proteins
  • Smad Proteins, Receptor-Regulated
  • Smad1 Protein
  • Smad1 protein, mouse
  • Smad4 Protein
  • Smad4 protein, mouse
  • Smad5 Protein
  • Smad5 protein, mouse

Associated data

  • GEO/GSE18629