Project Detail : PRJDB8407

AccessionPRJDB8407
Project TypePrimary submission
Project Data TypeEpigenomics, Transcriptome or Gene Expression

General info

Project titleKDM2B in polycomb repressive complex 1.1 functions as a tumor suppressor in the initiation of T- cell leukemogenesis
Project Description
KDM2B together with RING1B, PCGF1, and BCOR or BCORL1 comprise polycomb repressive complex 1.1 (PRC1.1), a non-canonical PRC1 that catalyzes H2AK119ub1. It binds to non-methylated CpG islands through its zinc finger-CxxC (ZF-CxxC) DNA binding domain and recruits the complex to target gene loci. Recent studies identified the loss of function mutations in the PRC1.1 gene, BCOR and BCORL1 in human T-cell acute lymphoblastic leukemia (T-ALL). We previously reported that Bcor insufficiency induces T-ALL in mice, supporting a tumor suppressor role for BCOR. However, the function of BCOR responsible for tumor suppression, either its co-repressor function for BCL6 or that as a component of PRC1.1, remains unclear. We herein examined mice specifically lacking the ZF-CxxC domain of KDM2B in hematopoietic cells. Similar to Bcor- deficient mice, Kdm2b-deficient mice developed lethal T-ALL mostly in a NOTCH1-dependent manner. A ChIP sequence analysis of thymocytes revealed the binding of KDM2B at promoter regions, at which BCOR and EZH2 co-localized. KDM2B target genes markedly overlapped with those of NOTCH1 in human T-ALL cells, suggesting that non-canonical PRC1.1 antagonizes NOTCH1-mediated gene activation. KDM2B target genes were expressed at higher levels than the others and were marked with high levels of H2AK119ub1 and H3K4me3, but low levels of H3K27me3, suggesting that KDM2B target genes are transcriptionally active or primed for activation. These results indicate that PRC1.1 plays a key role in restricting excessive transcriptional activation by active NOTCH1, thereby acting as a tumor suppressor in the initiation of T-cell leukemogenesis.
Release Date2019-06-06

Project Type

Sample scope/Material/Capture/Methodology

Sample ScopeMonoisolate
MaterialOther
CaptureOther
MethodologySequencing

Objective

ObjectiveEpigeneticMarkers, Expression

Target

Organism information

Organism nameMus musculus
Taxonomy ID10090