Fig. 7: Developmental gene regulation by EPOP through PRC2.1.
From: EPOP restricts PRC2.1 targeting to chromatin by directly modulating enzyme complex dimerization
a Volcano plot of differential gene expression. RNA-seq results of the EPOPD5 EpiLCs in triplicates were compared to those of the EPOPWT EpiLCs. The number of upregulated and downregulated genes is indicated. Data passing the FDR < 0.05, FC > 1.5, and average TPM of WT or mutant > 0.5 thresholds were analyzed. b Correlation of RNA-seq and ChIP-seq. One ChIP-seq replicate is shown here, and the other replicate is shown in the supplemental materials. The differential gene expression was aligned with the differential MTF2 enrichment around the transcription start site (TSS). The corresponding H3K27me3 signals are also displayed. Compared to the WT counterpart, 130 genes in the EPOPD5 EpiLCs were downregulated and associated with enhanced MTF2 signals around the TSS. The other 318 downregulated genes were not associated with EPOP-regulated MTF2 targeting. 187 upregulated genes are shown as well. c Gene ontology analysis. The PRC2.1-repressed, EPOP-maintained genes were subjected to gene ontology analysis on the DAVID server. The top 5 overrepresented terms in molecular function are shown. The p-value is one-tail Fisher Exact probability value used for gene-enrichment analysis by the DAVID server. d Schematic model of developmental gene repression by PRC2. On the left, the transient intrinsic dimer of the PRC2 core complex is illustrated. In the middle, distinct oligomerization states of various PRC2.1 and PRC2.2 holocomplexes are highlighted. MTF2 mediates direct chromatin binding, and it also stabilizes the intrinsic dimer, promoting chromatin targeting of the dimeric PRC2.1, likely via an avidity effect. EPOP disrupts the dimeric architecture of PRC2.1, containing MTF2, restricts PRC2.1 targeting, and thereby maintains the limited expression of PRC2.1-repressed developmental regulators. On the right, the PRC2.1-dependent role of EPOP in early development is illustrated. Black solid curve: during the ESC differentiation, a set of key gene regulators is repressed by PRC2.1, with limited expression being maintained by the EPOP-mediated inhibition of PRC2.1 targeting, which is followed by upregulation of the same set of gene regulators, leading to cell fate 1, e.g., PGCLCs. Gray dotted curve: the absence of EPOP results in the over-repression of these gene regulators by PRC2.1, which may change stem cell differentiation trajectories and result in an alternative cell fate 2. Some parts of the figure were created in BioRender. Liu, X. (2026) (https://biorender.com/l3ji249).
