The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3

PLoS Genet. 2013 Apr;9(4):e1003461. doi: 10.1371/journal.pgen.1003461. Epub 2013 Apr 18.

Abstract

Embryonic development is tightly regulated by transcription factors and chromatin-associated proteins. H3K4me3 is associated with active transcription and H3K27me3 with gene repression, while the combination of both keeps genes required for development in a plastic state. Here we show that deletion of the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) results in major neonatal lethality due to respiratory failure. Jarid1b knockout embryos have several neural defects including disorganized cranial nerves, defects in eye development, and increased incidences of exencephaly. Moreover, in line with an overlap of Jarid1b and Polycomb target genes, Jarid1b knockout embryos display homeotic skeletal transformations typical for Polycomb mutants, supporting a functional interplay between Polycomb proteins and Jarid1b. To understand how Jarid1b regulates mouse development, we performed a genome-wide analysis of histone modifications, which demonstrated that normally inactive genes encoding developmental regulators acquire aberrant H3K4me3 during early embryogenesis in Jarid1b knockout embryos. H3K4me3 accumulates as embryonic development proceeds, leading to increased expression of neural master regulators like Pax6 and Otx2 in Jarid1b knockout brains. Taken together, these results suggest that Jarid1b regulates mouse development by protecting developmental genes from inappropriate acquisition of active histone modifications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Embryonic Development
  • Genes, Developmental
  • Histones / metabolism
  • Jumonji Domain-Containing Histone Demethylases* / genetics
  • Mice
  • Nuclear Proteins / genetics
  • Polycomb-Group Proteins / genetics
  • Repressor Proteins* / genetics

Substances

  • Histones
  • Nuclear Proteins
  • Polycomb-Group Proteins
  • Repressor Proteins
  • Jumonji Domain-Containing Histone Demethylases

Grant support

MA was supported by an EMBO long-term postdoctoral fellowship. SMK was supported by a postdoctoral fellowship from the Netherlands Organisation for Scientific Research (NWO). The work in the Helin laboratory was supported by the Danish Medical Research Council, the Danish National Research Foundation, the Danish Cancer Society, the Novo Nordisk Foundation, the Lundbeck Foundation, and the Excellence Programme of the University of Copenhagen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.