Abstract
Trithorax group proteins methylate lysine 4 of histone 3 (H3K4) at active gene promoters. MLL5 protein, a member of the Trithorax protein family, has been implicated in the control of the cell cycle progression; however, the underlying molecular mechanism(s) have not been fully determined. In this study, we found that the MLL5 protein can associate with the cell cycle regulator "host cell factor" (HCF-1). The interaction between MLL5 and HCF-1 is mediated by the "HCF-1 binding motif" (HBM) of the MLL5 protein and the Kelch domain of the HCF-1 protein. Confocal microscopy showed that the MLL5 protein largely colocalized with HCF-1 in the nucleus. Knockdown of MLL5 resulted in reduced cell proliferation and cell cycle arrest in the G1 phase. Moreover, down-regulation of E2F1 target gene expression and decreased H3K4me3 levels at E2F1-responsive promoters were observed in MLL5 knockdown cells. Additionally, the core subunits, including ASH2L, RBBP5, and WDR5, that are necessary for effective H3K4 methyltransferase activities of the Trithorax protein complexes, were absent in the MLL5 complex, suggesting that a distinct mechanism may be used by MLL5 for exerting its H3K4 methyltransferase activity. Together, our findings demonstrate that MLL5 could associate with HCF-1 and then be recruited to E2F1-responsive promoters to stimulate H3K4 trimethylation and transcriptional activation, thereby facilitating the cell cycle G1 to S phase transition.
Highlights
Our findings demonstrate that MLL5 could associate with HCF-1 and be recruited to E2F1-responsive promoters to stimulate H3K4 trimethylation and transcriptional activation, thereby facilitating the cell cycle G1 to S phase transition
Our results demonstrate that the MLL5 protein could be recruited to E2F1-responsive promoters through association with HCF-1, and could stimulate H3K4 trimethylation at these promoters and facilitate transcriptional activation of E2F1 target genes during the G1 to S phase transition
We demonstrated that the MLL5 protein physically associated with the cell cycle regulator HCF-1 and the O-GlcNAc transferase OGT, and was recruited to E2F1responsive promoters to stimulate H3K4 trimethylation at the promoters and cause transcriptional activation of E2F1 target genes to facilitate the G1 to S phase transition
Summary
Our findings demonstrate that MLL5 could associate with HCF-1 and be recruited to E2F1-responsive promoters to stimulate H3K4 trimethylation and transcriptional activation, thereby facilitating the cell cycle G1 to S phase transition. Several recent studies on Mll gene knock-out mice have revealed that Mll is an important regulator of hematopoietic stem cells (10 –13) Both MLL and MLL5 have been implicated in the regulation of hematopoiesis, indicating that a common molecular mechanism might be used by these two Trithorax proteins. It has been reported that HCF-1 and the associated SET-1/MLL histone H3K4 methyltransferase complex can be recruited at transcription factor E2Fs-responsive promoters to facilitate cell cycle S phase progression or induce E2F1-mediated DNA damage and apoptosis [26, 27]. Our results reveal a novel molecular mechanism of MLL5 protein in the regulation of cell cycle progression at the G1/S phase
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