Inactive yet indispensable: the tale of Jarid2

Abstract

Methylation of histone tails is believed to be important for the establishment and inheritance of gene expression programs during development. Jarid2/Jumonji is the founding member of a family of chromatin modifiers with histone demethylase activity. Although Jarid2 contains amino acid substitutions that are thought to abolish its catalytic activity, it is essential for the development of multiple organs in mice. Recent studies have shown that Jarid2 is a component of the polycomb repressive complex 2 and is required for embryonic stem (ES) cell differentiation. Here, we discuss current literature on the function of Jarid2 and hypothesize that defects resulting from Jarid2 deficiency arise from a failure to correctly prime genes in ES cells that are required for later stages in development.

Figure 1

Jarid2 belongs to the JmjC-domain-containing family of proteins. (a) Several proteins that contain a JmjC domain catalyze the removal of methyl groups from lysine residues at specific positions on histone H3, as indicated. n.d., not determined. (b) Comparison of functional domains within the Jarid2 and Jarid1 proteins: Jumonji N (JmjN), AT-rich interaction domain (ARID), plant homeodomain zinc finger domain (PHD), Jumonji C (JmjC) and C5HC2 zinc finger (ZF). In addition, the N terminus of Jarid2 contains a nuclear localization sequence (aa 1–131) and a trans-repression domain (aa 132–222). (c) Amino acid sequence alignment of the JmjC domain of mouse Jarid1 and Jarid2 proteins. Asterisks indicate the amino acids that are critical for cofactor (iron and α-ketoglutarate) binding. Conserved amino acids are highlighted in grey. (d) Alignment of the amino acid sequence of the JmjC domains of Jarid2 proteins in different organisms; conserved residues are highlighted in grey.

Figure 2

Jarid2 is required for Ser5-phosphorylated RNAPII recruitment to bivalent domains in undifferentiated mouse ES cells. In pluripotent ES cells, establishment of primed chromatin involves the recruitment of Ser5-phosphorylated RNAPII (green) to the promoter regions (flag) of PRC-repressed target genes. PRC2 subunits (red) methylate H3K27, providing a docking site for PRC1 and Ring1A/B-mediated mono-ubiquitination of H2A (blue). Loss of PRC-mediated repression on ES cell differentiation results in productive gene expression. In Jarid2 null ES cells, Ser5-phosphorylated RNAPII is not efficiently recruited to PRC-repressed genes. This lack of priming results in the failure of mutant cells to efficiently express target genes when induced to differentiate.