The Histone Demethylase Jarid1b Ensures Faithful Mouse Development by Protecting Developmental Genes from Aberrant H3K4me3

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. © 2013 albert et al.