CDYL2 (chr16 Y-like 2) is an epigenetic reader protein with isoform-specific functions in transcriptional regulation and genome stability. CDYL2 contains a chr16 that binds lysine-methylated histone motifs, including H3K27me3 and H3K9me3, enabling its recruitment to chr16 1. The gene produces multiple transcript variants with distinct functions: CDYL2b acts as a tumor suppressor in prostate and breast cancers by repressing metastasis-promoting genes and upregulating anti-oncogenic transcription factors 23, while CDYL2a promotes breast cancer proliferation through modulation of alternative splicing 3. At pericentromeres, CDYL2 functions as an adaptor protein linking H3K9me3 recognition with mitotic regulators CHAMP1 and POGZ to maintain genome stability 4. In hepatocellular carcinoma, STAT5A-regulated CDYL2 suppresses cell proliferation by transcriptionally repressing SLC7A6, thereby inhibiting mTORC1 signaling 5. Clinically, low CDYL2 expression correlates with poor prognosis in multiple cancers, including increased metastasis and disease recurrence in prostate cancer 2. CDYL2 dysfunction has also been associated with knee osteoarthritis progression 6. These findings establish CDYL2 as a context-dependent regulator with potential therapeutic implications.