MBD6 (methyl-CpG binding domain protein 6) is a non-catalytic component of the polycomb repressive deubiquitinase (PR-DUB) complex that mediates epigenetic gene regulation. As part of the PR-DUB complex, MBD6 stabilizes complex components and stimulates deubiquitination of histone H2AK119ub1, promoting an open chr12 state 12. MBD6 associates with chr12 enriched in active histone marks (H3K4me1, H3K4me3, H3K27Ac) but not repressive marks (H3K27me3) 2. Notably, MBD6 does not bind methylated DNA directly; rather, it recognizes m5C on retrotransposon RNA to guide H2AK119ub deubiquitination 3. MBD6 recruits to heterochromatin through its methyl-binding domain independently of DNA methylation 4. Clinically, MBD6 dysfunction associates with multiple diseases. TET2-mutant leukemias depend on MBD6-mediated gene activation; MBD6 depletion selectively blocks TET2-mutant leukemic cell proliferation 3. MBD6 haploinsufficiency impairs mitochondrial respiration in autism spectrum disorder-associated contexts by dysregulating genes encoding mitochondrial proteins 5. MBD6 also regulates stemness and differentiation in adipose-derived stem cells downstream of Oct4 6. These findings identify MBD6 as a therapeutic target in TET2-mutant malignancies and reveal its role in neurodevelopmental and metabolic dysfunction.