JARID2

Official Full Name

jumonji and AT-rich interaction domain containing 2

Organism

Homo sapiens

GeneID

3720

Background

This gene encodes a Jumonji- and AT-rich interaction domain (ARID)-domain-containing protein. The encoded protein is a DNA-binding protein that functions as a transcriptional repressor. This protein interacts with the Polycomb repressive complex 2 (PRC2) which plays an essential role in regulating gene expression during embryonic development. This protein facilitates the recruitment of the PRC2 complex to target genes. Alternate splicing results in multiple transcript variants. Mutations in this gene are associated with chronic myeloid malignancies. [provided by RefSeq, May 2012]

Synonyms

JMJ; DIDDF;

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Detailed Information

Recent Research

JARID2 belongs to JmjC domain containing protein family, members of which mediate histone demethylation through an iron-and α-ketoglutarate (KG)-dependent oxidation mechanism. In fact, JARID2, an essential regulatory component of PRC2 in pluripotent stem cells, contains an RNA-binding region that mediates, at least in part, its interaction with the imprinted lncRNA MEG3. Moreover, Jarid2, the founding member of the Jumonji family of proteins in the targeting of PRC2 to the X chromosome during early XCI, is transiently associated, via its N-terminal region, with the Xist RNA-coated chromosome during early development. Although JARID2 target sites are enriched for CGG- and GA-containing sequences, its DNA binding preferences lack the specificity to explain its distribution on chromatin. JARID2 and MTF2 were reported to be identified as PRC2 interacting proteins with affinity purification and genome-wide screen approaches. JARID2, MTF2, and esPRC2p48 represent integral subunits of PRC2 in ES cells and that all three subunits are required to maximally stimulate the histone methyl transferase activity of PRC2 in vitro. Jarid2 is implicated in the initial xist-induced targeting of PRC2 to the inactive X chromosome. The region containing the conserved B and F repeats of Xist is critical for Jarid2 recruitment via its unique N-terminal domain. Xist-induced Jarid2 recruitment occurs chromosome-wide independently of a functional PRC2 complex, unlike at other parts of the genome, such as CG-rich regions, where Jarid2 and PRC2 binding are interdependent. Therefore, Jarid2 represents an important intermediate between PRC2 and Xist RNA for the initial targeting of the PRC2 complex to the X chromosome during onset of XCI.

Jarid2 up-regulation in miR-155-deficient Th17 cells resulted in widespread increased recruitment of the Jarid2-PRC2 holoenzyme that coincided with increased deposition of H3K27me3 at specific sites throughout the genome. Lack of Jarid2 results in enhanced Th17 cytokine gene expression. Jarid2 is required for PRC2 recruitment and transcriptional silencing of Th17 cell associated genes. Knockdown of JARID2, MTF2 or esPRC2p48 altered the level of PRC2-mediated H3K27 methylation, a significant increase in TGFβR2 gene and GATA1 gene expression, and led to expression of differentiation-related genes in ES cells. In contrast, JARID2 was knocked down by shRNA, and protein levels of MTF2, esPRC2p48 and SUZ12 were significantly reduced. Knockout of JARID2, MTF2 or esPRC2p48 resulted in a significant increase in the expression of all examined Hox genes. Knockdown of JARID2, MTF2, esPRC2p48 or SUZ12 resulted in a decrease in the specificity of H3K27 trimethylation, but had no effect on H3K27 mono- and dimethylation at the promoter of the TGFβR2 gene.

JARID2 may have acquired an additional layer of regulation in vertebrates. JARID2 binds to RNA in vitro. Jarid2 was recently discovered to be essential for recruiting PRC2 to genomic sites in embryonic stem (ES) cells. Some reports show that miR-155 and Jarid2 form a regulatory circuit that can control lineage specific gene expression in CD4+ T cells through its effect on Polycomb recruitment. Jarid2 recruits the histone modifying holoenzyme PRC2 to specific sites in the genome and silences transcription of its target genes through histone 3 lysine 27 (H3K27) trimethylation mediated by the polycomb proteins enhancer of zeste homolog 1 (Ezh1) or Ezh2.Some reports indicate that in the absence of JARID2, PRC2 is recruited late and incompletely to its target genes and its enzymatic function is diminished, which results in failure to follow the differentiation program. Without JARID2 the interaction between Meg3 and PRC2 is much weaker , suggesting that of the two contact points, the one on JARID2 makes the larger contribution to the affinity for Meg3. There is a model in which some lncRNAs function as scaffold to stimulate assembly of PRC2 at JARID2 target sites(Figure 1).

JARID2 Figure 1.A model in which some IncRNAs function as scaffold to stimulate assembly of PRC2 at JARID2 target sites (Syuzo Kaneko1, et al. 2014).

JARID2, MTF2, and esPRC2p48 play important roles in regulating PRC2 catalyzed H3K27 methylation in vivo. Jarid2 is critical for recruitment of core PRC2 factors to the Xist-coated chromosome but is not required for the erasure of euchromatic marks, for PRC1-mediated H2Aub during the early stages of XCI. Jarid2 is a partner of the Xi, being recruited transiently at the onset of XCI, within the same time window as PRC2. JARID2, MTF2, and esPRC2p48 repress lineage-specific gene expression during somatic cell reprograming. Furthermore, JARID2 exhibited strong interactions with peptides containing H3K4me2 and H3K9me2. Expression of JARID2, MTF2, and esPRC2p48 together, but not individually, enhances Oct4/Sox2/Klf4-mediated reprograming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells, whereas knockdown or knockout of JARID2, MTF2, or esPRC2p48 significantly inhibits reprograming.

References:

Kaneko S, et al. Interactions between JARID2 and noncoding RNAs regulate PRC2 recruitment to chromatin.Molecular Cell, 2014, 53(2):290-300.
Zhang Z, et al. PRC2 Complexes with JARID2, MTF2, and esPRC2p48 in ES Cells to Modulate ES Cell Pluripotency and Somatic Cell Reprograming. Stem Cells, 2015, 29(2):229-240.
DarochaS,et al. Jarid2 Is Implicated in the Initial Xist-Induced Targeting of PRC2 to the Inactive X Chromosome. Molecular Cell, 2014, 53(2):301-316.
Escobar T M, et al. miR-155 activates cytokine gene expression in Th17 cells by regulating the DNA-binding protein Jarid2 to relieve Polycomb-mediated repression. Immunity, 2014, 40(6):865-879.

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