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.
Highlights
Embryonic development is characterized by a coordinated program of proliferation and differentiation that is tightly regulated by transcription factors and chromatin-associated proteins
Histone modifications are involved in transcriptional regulation and affect cellular identity, differentiation, and development
We study the histone demethylase Jarid1b (Kdm5b/Plu1), as it has been reported to be highly expressed in several human cancers and might present a novel target for anti-cancer therapies
Summary
Embryonic development is characterized by a coordinated program of proliferation and differentiation that is tightly regulated by transcription factors and chromatin-associated proteins. Certain genes are activated while others are repressed, resulting in a unique pattern of gene expression in each cell type. Methylation of H3K4 is catalyzed by a family of 10 histone methyltransferases in mammals [4]. Five of these are members of the Trithorax group of proteins that were first described in Drosophila to be required for maintenance of Hox gene expression by counteracting Polycomb-mediated repression. In Mll and Mll mutant mice, target genes are properly activated but expression fails to be maintained leading to embryonic lethality [5,6]. H3K4 histone methyltransferases function in hematopoiesis [7,8] and neurogenesis [9]
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