| JARID1C (also known as KDM5C or SMCX) is a histone demethylase of the JARID1/KDM5 family that belongs to the larger JmjC‑domain‑containing class of lysine‑demethylating enzymes and functions as an H3K4me3/me2‑specific eraser of transcription‑activating marks. It contains a JmjC catalytic domain, a JmjN domain, a BRIGHT domain, a C5HC2 zinc‑finger region, and multiple PHD domains that bind methylated histone tails, including H3K4me3, and these modules together enable sequence‑specific recruitment to chromatin and cooperative regulation of target promoters. JARID1C is a core component of repressive complexes that include HDAC1, HDAC2, G9a (EHMT2), and the transcription factor REST, and through this association, it binds REST‑responsive elements in non‑neuronal cells and stem cells to silence neuronal‑specific genes such as BDNF, SCG10, and SCN2A, thereby preventing premature neuronal differentiation and maintaining non‑neural lineage identity. By demethylating H3K4me3 and H3K4me2 at these loci, JARID1C reduces RNA Polymerase II occupancy and transcriptional output, linking its enzymatic activity directly to chromatin‑condensed, low‑expression states. In humans, JARID1C is X‑linked, and mutations in the JARID1C gene are associated with X‑linked intellectual disability, short stature, hyperreflexia, and epilepsy, and many disease‑linked variants map to the JmjC domain, impairing demethylase activity or complex‑binding capacity. In several cancers, including clear‑cell renal cell carcinoma, reduced JARID1C function correlates with derepression of growth‑promoting loci and genomic instability, and in other contexts, JARID1C has been shown to repress HPV E6/E7 oncogenes. |
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