Abstract
Polycomb group (PcG) of proteins are a group of highly conserved epigenetic regulators involved in many biological functions, such as embryonic development, cell proliferation, and adult stem cell determination. PHD finger protein 19 (PHF19) is an associated factor of Polycomb repressor complex 2 (PRC2), often upregulated in human cancers. In particular, myeloid leukemia cell lines show increased levels of PHF19, yet little is known about its function. Here, we have characterized the role of PHF19 in myeloid leukemia cells. We demonstrated that PHF19 depletion decreases cell proliferation and promotes chronic myeloid leukemia (CML) differentiation. Mechanistically, we have shown how PHF19 regulates the proliferation of CML through a direct regulation of the cell cycle inhibitor p21. Furthermore, we observed that MTF2, a PHF19 homolog, partially compensates for PHF19 depletion in a subset of target genes, instructing specific erythroid differentiation. Taken together, our results show that PHF19 is a key transcriptional regulator for cell fate determination and could be a potential therapeutic target for myeloid leukemia treatment.
Highlights
Cell fate decisions rely on the precise control of specific transcription programs, which are governed by multiple layers of regulation
To gain insights into why MTF2 is increasingly deposited in a subset of targets, we studied their epigenetic status in control conditions: as depicted in Figure 4E, the ChIP-seq levels of MTF2, PHF19, H3K27me3, and EZH2 were higher in the top 200 MTF2 target genes with respect to the rest, indicating they were significantly occupied by Polycomb repressor complex 2 (PRC2) prior to PHF19 depletion
The role of PRC2 in leukemia has been studied (Carlo et al, 2019), and in particular, the catalytic PRC2 core component EZH2 has been reported to be overexpressed in chronic myeloid leukemia (CML) (Xie et al, 2016)
Summary
Cell fate decisions rely on the precise control of specific transcription programs, which are governed by multiple layers of regulation. The epigenetic status of genes and their regulatory regions are paramount, because of their direct impact on expression and for its reversible nature that allows a progressive fine-tuning control of expression along differentiation. The Polycomb group of proteins is one of the most important players in epigenetic regulation. They form multimeric complexes in the nucleus that associate with and modify the chromatin landscape. The Polycomb repressor complex 2 (PRC2) catalyzes the trimethylation of lysine 27 on the histone H3 N-terminal tail (H3K27me3), which is associated with chromatin compaction and gene repression (Schuettengruber et al, 2017).
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