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JARID1C belongs to the JARID subfamily of JmjC containing proteins, together with RBP2 (JARID1A), PLU-1 (JARID1B) and SMCY (JARID1D). In fact, the JmjC domain of JARID1C represents its catalytic moiety that specifically demethylates di- and trimethylated lysine 4 on histone 3 in a Fe(II) and -ketoglutarate-dependent manner. Moreover, JARID1C contains also a BRIGHT domain and an ATrich domain interacting domain (ARID) that binds DNA. JARID1C is expressed in multiple human tissues, has a paralogue on the Y chromosome and is highly conserved across evolution. Indeed, JARID1C is one of the few genes on the X chromosome escaping X-inactivation. The missense, frameshift and nonsense mutations of JARID1C are associated with X-linked mental retardation (XLMR). JARID1C and histone demethylase is required for proper DNA replication, by the removal of methyl groups from H3K4 residues on actively replicating early origins. JARID1C binds broadly to chromatin domains, which is a histone mark enriched in heterochromatin. Some reports show that JARID1C localizes on heterochromatin, is required for heterochromatin replication, and forms a complex with established players of heterochromatin assembly, including SUV39H1 and HP1α, as well as with proteins not previously associated with heterochromatin assembly, such as the cullin 4 (CUL4) complex adaptor protein DDB1.
JARID1C was among 485 chromatin factors, which enriched at nascent versus mature postreplicative chromatin. Moreover, there is an interaction between JARID1C and PCNA through its PIP (PCNA-interaction protein) motif. Some reports show that cells devoid of JARID1C fail to efficiently enter and progress through the S phase. JARID1C is regulated by cell cycle and localizes at sites of DNA synthesis. Some studies indicate that silencing of JARID1C with two different shRNAs increased H3K4me3 levels at all the three active early-replicating origins tested. However, H3K4me3 levels on flanking regions were only modestly affected by JARID1C knockdown. JARID1C reduction did not impact on the levels of H3K4me3 on early replicating Top1 and MCM4 origins. JARID1C down-regulation did not affect the total levels of MCM2 and MCM5 present in the cells. Furthermore, JARID1C is not involved in fork licensing. JARID1C regulates CDC45 binding to chromatin independently from CDK1 activity. JARID1C loss unleashes the expression of heterochromatic noncoding RNAs (ncRNAs), thus triggering genomic instability. Upon JARID1C downregulation a consistent subgroup of origins failed to be activated. JARID1C knockdown reduced the loading of CDC45 on chromatin of S -phase cells. JARID1C downregulation impacts DNA replication and more specifically origin firing. Instead, fork activation and histone H4 acetylation, additional early events involved in DNA replication, are not affected by JARID1C downregulation.
JARID1C and KDM6A mutations were not associated with OS (overall survival). JARID1C dictates the assembly of the pre-initiation complex, driving the binding to chromatin of the pre-initiation proteins CDC45 and PCNA, through the demethylation of the histone mark H3K4me3. In addition, JARID1C exerts a prominent role in neuronal development and function. Indeed, silencing of JARID1C expression in zebrafish causes brain-patterning defects as well as impaired dendrite development and significant neuronal cell death in rat neurons. JARID1C contributes to neuro-development through transcriptional repression. Several reports have underlined that JARID1C inactivation drives the unregulated expression of heterochromatic ncRNAs, which causes genomic instability and is associated with increased chromosomal rearrangements in ccRCC patients, ultimately leading to a shorter overall survival (Figure 1).
Figure 1. Proposed model for JARID1C-mediated heterochromatin assembly and silencing of ncRNAs at every cell cycle.
JARID1C positively regulates origin function through histone 3 lysine 4 demethylation at DNA replication origins. As such, JARID1C demethylase activity promotes the timely formation of the pre-IC complex shepherding the binding of CDC45 and PCNA to chromatin. JARID1C-mediated H3K4me3 demethylation is a required step for proper origin functionality in metazoans. JARID1C contributes to proper CMG formation and efficient PCNA loading on chromatin through H3K4me3 demethylation. Silencing of JARID1C strictly phenocopies initiation mutants. JARID1C inactivation led to the unrestrained expression of heterochromatic ncRNAs that in turn triggered genomic instability. In mouse embryonic stem cells and in neuronal progenitor cells, JARID1C is recruited on regulatory regions such as enhancers and promoters.