GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE270nnn/GSE270991/primaryOK200GenomicsHomo sapiensGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE270991GEOGSEfalseL3MBTL2 maintains MYCN-amplified neuroblastoma cell proliferation through silencing NRIP3 and BRME1 genes [NB1_NGP_KO]Epigenetic alterations critically affect tumor development. Polycomb-group complexes constitute an evolutionarily conserved epigenetic machinery that regulates stem cell fate and development. They are implicated in tumorigenesis, primarily via histone modification. Canonical and non-canonical Polycomb repressive complex 1 (PRC1.1–6) mediate the ubiquitination of histone H2A on lysine 119 (H2AK119ub). Here, we studied the functional roles of L3MBTL2, one of the PRC1.6 molecules, in neuroblastoma (NB) cells. shRNA- and CRISPR/Cas9-mediated L3MBTL2 depletion caused NB cell growth inhibition, cell-cycle arrest, and γ-H2A.X upregulation. Moreover, the knockout of L3MBTL2 profoundly suppressed xenograft tumor formation. Transcriptome analysis identified Break repair meiotic recombinase recruitment factor 1 (BRME1) and nuclear receptor interacting protein 3 (NRIP3) as targets of L3MBTL2-mediated silencing. The deletion of L3MBTL2 reduced enrichment of H2AK119ub and PCGF6 at transcriptional start site proximal regions of the targets. Add-back studies unveiled the importance of L3MBTL2-BRME1 and -NRIP3 axes for NB cell proliferation. We further manifested the association of MYCN with de-repression of NRIP3 in an L3MBTL2-deficient context. Therefore, this study first revealed the significance of L3MBTL2-mediated gene silencing in MYCN-amplified NB cells.2026/06/16GSE270991GSM8366769GSM8366768GSM8366767GSM8366766GSM8366765GSM8366764GSM8366775GSM8366774GSM8366773GSM8366772GSM8366771GSM836677018573270991Homo sapiens