Alternative titles; symbols
HGNC Approved Gene Symbol: JARID2
Cytogenetic location: 6p22.3 Genomic coordinates (GRCh38): 6:15,246,069-15,522,042 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.3 | Developmental delay with variable intellectual disability and dysmorphic facies | 620098 | Autosomal dominant | 3 |
The JARID2 gene encodes a transcriptional repressor protein that regulates the activity of various histone methyltransferase complexes, affecting epigenetic changes that control gene expression during development, cellular differentiation, and morphogenesis (summary by Verberne et al., 2022).
Berge-Lefranc et al. (1996) isolated clones highly homologous to the mouse gene Jumonji from a human embryonic cDNA library. In mouse, Jumonji (Jmj) is required for neural tube formation. Berge-Lefranc et al. (1996) reported that the human jumonji (JMJ) and mouse Jmj gene products are 90% identical. Northern blot analysis revealed a low level of expression of JMJ in all human embryonic and adult tissues analyzed. In situ hybridization studies on embryonic slices revealed high levels of expression in dorsal root ganglia neurons. The authors detected high levels of expression in adult cerebral cortex.
Toyoda et al. (2000) determined that JMJ is expressed as a 160-kD protein by Western blot analysis. Immunofluorescence and Western blot analysis demonstrated that JMJ specifically localizes to the cell nucleus.
Toyoda et al. (2000) found that overexpression of JMJ appeared to inhibit cell growth, whereas Jmj-deficient mice had cell growth enhancement.
Pasini et al. (2010) showed that the Polycomb repressive complex-2 (PRC2) forms a stable complex with JARID2. Using genomewide location analysis, Pasini et al. (2010) showed that JARID2 binds to more 90% of previously mapped Polycomb group target genes. The authors found that JARID2 is sufficient to recruit Polycomb group proteins to a heterologous promoter, and that inhibition of JARID2 expression leads to a major loss of Polycomb group binding and to a reduction of histone H3 lysine-27 trimethylation (H3K27me3) levels on target genes. Consistent with an essential role for Polycomb group proteins in early development, Pasini et al. (2010) demonstrated that JARID2 is required for the differentiation of mouse embryonic stem cells. Pasini et al. (2010) concluded that JARID2 is essential for the binding of Polycomb group proteins to target genes and, consistent with this, for the proper differentiation of embryonic stem cells and normal development.
Using chromatin immunoprecipitation sequencing data, Escobar et al. (2014) found that microRNA-155 (MIR155; 609337) was bound by Th17 (see IL17, 603149) transcription factors. Mouse Th17 and regulatory T cells lacking Mir155 expressed increased amounts of Jarid2. PRC2 binding to chromatin and H3K27 methylation were increased in Mir155-deficient mouse cells, coinciding with failure to express Il22 (605330), Il10 (124092), Il9 (146931), and Atf3 (603148). Defective Th17 cytokine expression and Treg cell homeostasis in cells lacking Mir155 could be partially suppressed by deletion of Jarid2. Escobar et al. (2014) concluded that MIR155 contributes to Th17 cell function by suppressing the inhibitory effects of JARID2.
Cryoelectron Microscopy
Kasinath et al. (2018) reported the cryoelectron microscopy structures of human PRC2 in a basal state and 2 distinct active states while in complex with its cofactors JARID2 and AEBP2 (617934). Both cofactors mimic the binding of histone H3 tails. JARID2, methylated by PRC2, mimics a methylated H3 tail to stimulate PRC2 activity, whereas AEBP2 interacts with the RBAP48 (RBBP4; 602923) subunit, mimicking an unmodified H3 tail. SUZ12 (606245) interacts with all other subunits within the assembly and thus contributes to the stability of the complex.
Berge-Lefranc et al. (1996) mapped the human JMJ gene to chromosome 6p24-p23 using autoradiographic in situ hybridization.
Stumpf (2022) mapped the JARID2 gene to chromosome 6p22.3 based on an alignment of the JARID2 sequence (GenBank AK303610) with the genomic sequence (GRCh38).
In 2 unrelated patients (P4 and P5) with developmental delay with variable intellectual disability and dysmorphic facies (DIDDF; 620098), Verberne et al. (2022) identified de novo heterozygous point mutations in the JARID2 gene (601594.0001 and 601594.0002). One was predicted to result in a frameshift and the other in a splicing defect. Six additional individuals, including a mother and daughter (patients 6 and 7), with a similar phenotype were found to carry heterozygous intragenic deletions within the JARID2 gene. These deletions varied in size and occurred de novo in 4 cases. Functional studies of the variants and deletions were not performed, but all were predicted to result in haploinsufficiency. By assessing peripheral blood DNA methylation profiles, Verberne et al. (2022) identified a specific episignature in the 8 patients that was different from that of 56 controls. This DNAm episignature was associated with increased methylation at 150 probes in JARID2-haploinsufficient cells compared to controls. No differentially methylated regions (DMRs) were detected in the episignature, and gene set enrichment analysis did not yield consistent associated molecular pathways. Additional studies using this method excluded the specific episignature in 3 individuals who carried heterozygous missense variants of uncertain significance (R788Q and E644K) in the JARID2 gene, suggesting that they may not be pathogenic. The authors noted the small sample size, but suggested that the distinct episignature could be used as a biomarker for this syndrome. Several of the patients had previously been reported by Verberne et al. (2021).
Toyoda et al. (2003) found that Jmj was highly expressed in developing mouse cardiac ventricles, with higher expression in the trabecular layer than in the compact layer. Jmj deficiency in mice caused hyperproliferation of embryonic trabecular myocytes. Jmj-deficient embryos showed enhanced expression of cyclin D1 (CCND1; 168461), but no other cyclin examined. Toyoda et al. (2003) found that Jmj bound and repressed the cyclin D1 promoter when expressed in COS-7 cells, and mutation analysis indicated that the N-terminal 220 amino acids of Jmj had repressor activity. Inactivation of cyclin D1 rescued the cardiac hyperproliferation defect in Jmj-deficient embryos. Toyoda et al. (2003) concluded that JMJ downregulates cardiac cell proliferation by repressing cyclin D1 expression.
Jmj-deficient mice show several morphologic abnormalities, including neural tube and cardiac defects, and die in utero around embryonic day 11.5. By exogenous expression of Jmj in the heart of Jmj-deficient mice, Takahashi et al. (2004) rescued the morphologic phenotype in heart, and these embryos survived until embryonic day 13.5. They concluded that at least 2 lethal periods exist in Jmj mutant mice, with cardiac abnormalities causing the earlier lethality.
In a 14-year-old boy (patient 4) with developmental delay with variable intellectual disability and dysmorphic facies (DIDDF; 620098), Verberne et al. (2022) identified a de novo heterozygous 1-bp duplication (c.2866dupG, NM_004973.4) in exon 13 of the JARID2 gene, predicted to result in a frameshift and premature termination (Glu956GlyfsTer72). Patient peripheral blood cells showed a specific DNAm episignature that differed from those of 56 controls and was associated with increased methylation at 150 probes. The patient had been reported as individual 9 in the paper by Verberne et al. (2021).
In a 5-year-old boy (patient 5) with developmental delay with variable intellectual disability and dysmorphic facies (DIDDF; 620098), Verberne et al. (2022) identified a de novo heterozygous G-to-C transversion (c.2731+1G-C, NM_004973.4) in intron 11 of the JARID2 gene, predicted to result in a splicing defect. The variant was not present in the gnomAD database. Patient peripheral blood cells showed a specific DNAm episignature that differed from those of 56 controls and was associated with increased methylation at 150 probes. The patient had been reported as individual 13 in the paper by Verberne et al. (2021).
Berge-Lefranc, J.-L., Jay, P., Massacrier, A., Cau, P., Mattei, M. G., Bauer, S., Marsollier, C., Berta, P., Fontes, M. Characterization of the human jumonji gene. Hum. Molec. Genet. 5: 1637-1641, 1996. [PubMed: 8894700] [Full Text: https://doi.org/10.1093/hmg/5.10.1637]
Escobar, T. M., Kanellopoulou, C., Kugler, D. G., Kilaru, G., Nguyen, C. K., Nagarajan, V., Bhairavabhotla, R. K., Northrup, D., Zahr, R., Burr, P., Liu, X., Zhao, K., Sher, A., Jankovic, D., Zhu, J., Muljo, S. A. miR-155 activates cytokine gene expression in Th17 cells by regulating the DNA-binding protein Jarid2 to relieve polycomb-mediated repression. Immunity 40: 865-879, 2014. [PubMed: 24856900] [Full Text: https://doi.org/10.1016/j.immuni.2014.03.014]
Kasinath, V., Faini, M., Poepsel, S., Reif, D., Feng, X. A., Stjepanovic, G., Aebersold, R., Nogales, E. Structures of human PRC2 with its cofactors AEBP2 and JARID2. Science 359: 940-944, 2018. [PubMed: 29348366] [Full Text: https://doi.org/10.1126/science.aar5700]
Pasini, D., Cloos, P. A. C., Walfridsson, J., Olsson, L., Bukowski, J.-P., Johansen, J. V., Bak, M., Tommerup, N., Rappsilber, J., Helin, K. JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature 464: 306-310, 2010. [PubMed: 20075857] [Full Text: https://doi.org/10.1038/nature08788]
Stumpf, A. M. Personal Communication. Baltimore, Md. 11/02/2022.
Takahashi, M., Kojima, M., Nakajima, K., Suzuki-Migishima, R., Motegi, Y., Yokoyama, M., Takeuchi, T. Cardiac abnormalities cause early lethality of jumonji mutant mice. Biochem. Biophys. Res. Commun. 324: 1319-1323, 2004. [PubMed: 15504358] [Full Text: https://doi.org/10.1016/j.bbrc.2004.09.203]
Toyoda, M., Kojima, M., Takeuchi, T. Jumonji is a nuclear protein that participates in the negative regulation of cell growth. Biochem. Biophys. Res. Commun. 274: 332-336, 2000. [PubMed: 10913339] [Full Text: https://doi.org/10.1006/bbrc.2000.3138]
Toyoda, M., Shirato, H., Nakajima, K., Kojima, M., Takahashi, M., Kubota, M., Suzuki-Migishima, R., Motegi, Y., Yokoyama, M., Takeuchi, T. jumonji downregulates cardiac cell proliferation by repressing cyclin D1 expression. Dev. Cell 5: 85-97, 2003. [PubMed: 12852854] [Full Text: https://doi.org/10.1016/s1534-5807(03)00189-8]
Verberne, E. A., Goh, S., England, J., van Ginkel, M., Rafael-Croes, L., Maas, S., Polstra, A., Zarate, Y. A., Bosanko, K. A., Pechter, K. B., Bedoukian, E., Izumi, K., and 28 others. JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. Genet. Med. 23: 374-383, 2021. [PubMed: 33077894] [Full Text: https://doi.org/10.1038/s41436-020-00992-z]
Verberne, E. A., van der Laan, L., Haghshenas, S., Rooney, K., Levy, M. A., Alders, M., Maas, S. M., Jansen, S., Lieden, A., Anderlid, B.-M., Rafael-Croes, L., Campeau, P. M., and 12 others. DNA methylation signature for JARID2-neurodevelopmental syndrome. Int. J. Molec. Sci. 23: 8001, 2022. [PubMed: 35887345] [Full Text: https://doi.org/10.3390/ijms23148001]