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

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.

Histone Demethylase Jumonji AT-rich Interactive Domain 1B (JARID1B) Controls Mammary Gland Development by Regulating Key Developmental and Lineage Specification Genes

“…In this study, we demonstrated that JARID1B is critical for the recruitment of GATA3 to the Foxa1 promoter and its transcriptional activation. As an H3K4me3/2 demethylase, JARID1B binding at the gene promoters can lead to decreased gene expression (19,39), but its recruitment to the intragenic regions (40) or enhancers (41) was shown to activate gene expression. In mammary epithelial cells, JARID1B loss induced a decrease rather than an increase in H3K4me3 levels at many of its target promoters.…”

“…In previously generated Jarid1b Ϫ/Ϫ mouse models, embryonic lethality and severe neonatal defects hindered the study of JARID1B functions in the mammary gland and other adult tissues (12,19). The reduced number of viable Jarid1b ϩ/Ϫ mice reported by Catchpole et al (12) suggests that the embryonic lethality they observed in association with disruption of the Jarid1b locus might be due to the neomycin cassette carried by the ES clones that were used to generate the line.…”

“…strains (12,19) suggest that genetic background could contribute to the differences in phenotypes. We then backcrossed these animals to both FVB/N and C57BL/6 backgrounds.…”

“…In contrast, a strain of Jarid1b Ϫ/Ϫ mice generated using a different targeting construct showed neonatal lethality due to abnormal respiratory function as well as skeletal and neuronal development defects (19). These defects were linked to the accumulation of H3K4me3 and activation of neural master regulators like Pax6 and Otx2 (19). Another mouse strain that expresses JARID1B with ARID deletion (⌬ARID) exhibited a largely normal phenotype with the exception of delayed mammary gland development (12).…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…Recent studies described that besides being a potent inhibitor of jumonji proteins, with activity toward H3K27me3/me2 (KDM6), GSK-J1 can also inhibit KDM5 activity on H3K4me3/me2 in U2OS cells in vitro. 141 Considering the effect of JMJD3 on several biologic functions (e.g., inflammatory response in macrophages 107 ) and those of KDM5, 142 optimizing the dose and frequency of administration of such inhibitors to maximize the therapeutic window and limit toxicity will be a key factor for reaching a successful clinical outcome. The combination of agents with different mechanisms of action, as recently proposed 117 may offer a better chance for tumor control with limited toxicity.…”