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L3MBTL2 maintains MYCN-amplified neuroblastoma cell proliferation through silencing NRIP3 and BRME1 genes [NB1_NGP_KO]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270991 | GEO | 2026/06/16

REPOSITORIES: GEO

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Project description:Human MBT domain‐containing protein L3MBTL2 was found to be an integral component of a protein complex that we termed Polycomb Repressive Complex 1‐like 3 (PRC1L3) given the presence of the PcG proteins RING1, RING2 and PCGF6. L3MBTL2 binds chromatin in a histone modification‐ independent manner and is required for the repressive function of PRC1L3. PRC1L3 also contains E2F6 and CBX3, two factors with well‐established functions in transcriptional repression. Genome‐wide profiling identified several hundred genes that are simultaneously bound by L3MBTL2 and E2F6, preferentially around transcriptional start sites. Importantly, these genes are largely distinct from those targeted by other E2Fs or L3MBTL, another MBT‐domain containing protein that interacts with RB1. H3K27 or H3K9 methylation, two chromatin modifications implicated in gene silencing, are not present on all L3MBTL2 target genes. L3MBTL2‐specific RNAi results in altered target gene expression patterns and affects the differentiation program of hematopoietic cells. Our data suggest that repression of transcription via chromatin modulation, reflective of PRC1 function, can be achieved by multiple players and does not necessarily require the presence of histone lysine methylation marks. 12 total ChIP-seq datasets; one E2F6 dataset and one Input dataset done from MCF7 cells on Nimblegen ENCODE arrays; one L3MBTL1 dataset and one Input dataset done from MCF7 cells on Nimblegen ENCODE arrays; one L3MBTL2 dataset and one Input dataset done from MCF7 cells on Nimblegen ENCODE arrays; one E2F6 dataset and one Input dataset done from MCF7 cells on Nimblegen 1.5kb promoter arrays; one L3MBTL1 dataset and one Input dataset done from MCF7 cells on Nimblegen 1.5kb promoter arrays; one L3MBTL2 dataset and one Input dataset done from MCF7 cells on Nimblegen 1.5kb promoter arrays.

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L3MBTL2 maintains MYCN-amplified neuroblastoma cell proliferation through silencing NRIP3 and BRME1 genes [NB1_NGP_KO]

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