Figure 4.
Loss of PRC1.1 leads to epigenetic reactivation of a unique group of noncanonical menin targets upon menin inhibition. (A) K-means clustering of differentially expressed genes in OCI-AML2 cells treated with DMSO or 1 μM VTP50469 for 6 days. Two replicates were used for each group. The list of representative genes and enrichment annotations for each cluster are shown on the right. (B) Normalized read counts for menin-MLL canonical target genes PBX3, MEIS1, and MEF2C in OCI-AML2 cells expressing sgLuc, sgPCGF1, and sgBCOR, followed by a 6-day treatment with DMSO or 1 μM VTP50469. Data were obtained from 2 biological replicates for each group. (C) Chromatin immunoprecipitation (ChIP) enrichment analysis of transcription factor target gene sets in cluster 4 genes as shown in panel A. (D) Heat map showing menin and H2AK119ub ChIP sequencing (ChIP-seq) peaks and their overlaps at transcription start sites of genes in indicated OCI-AML2 cells subjected to a 6-day treatment with DMSO or 1 μM VTP50469. (E) Averaged menin and H2AK119ub ChIP-seq signals over ±3 kb from transcription start sites of menin-specific target genes (left) and menin/H2AK119ub–shared target genes (right) in indicated OCI-AML2 cells subjected to a 6-day treatment with DMSO or 1 μM VTP50469. (F) Schematic illustrating the definition of type I and type II menin target genes. (G) Boxplots showing log2 ratio of menin signal to H2AK119ub signal within ±3 kb of the transcription start sites of type I and II menin target genes. (H) Boxplots illustrating the rescue indices of type I and II menin target genes. A rescue index value of 0 indicates no rescue effect, whereas a value of 1 denotes complete rescue. (I) Scatterplot showing a negative correlation between the rescue index and the signal balance of menin and H2AK119ub, represented by the log2-ratio of menin signal to H2AK119ub signal (top). Boxplots showing the log2FC in gene expression in the indicated OCI-AML2 cells compared with DMSO-treated sgLuc-expressing cells (bottom). Displayed are the top 10% of genes with the most balanced signals (left) and the top 10% of menin-dominant genes. (J) Menin and H2AK119ub ChIP-seq and RNA-seq profiles of representative type I and type II menin targets in indicated OCI-AML2 cells. (K) Schematic models depicting the mechanisms of transcriptional regulation by menin and PRC1.1-mediated H2AK119ub at type I and type II menin target genes. D, DMSO; RNA-seq, RNA sequencing; TSS, transcription start site; V, VTP50469.

Loss of PRC1.1 leads to epigenetic reactivation of a unique group of noncanonical menin targets upon menin inhibition. (A) K-means clustering of differentially expressed genes in OCI-AML2 cells treated with DMSO or 1 μM VTP50469 for 6 days. Two replicates were used for each group. The list of representative genes and enrichment annotations for each cluster are shown on the right. (B) Normalized read counts for menin-MLL canonical target genes PBX3, MEIS1, and MEF2C in OCI-AML2 cells expressing sgLuc, sgPCGF1, and sgBCOR, followed by a 6-day treatment with DMSO or 1 μM VTP50469. Data were obtained from 2 biological replicates for each group. (C) Chromatin immunoprecipitation (ChIP) enrichment analysis of transcription factor target gene sets in cluster 4 genes as shown in panel A. (D) Heat map showing menin and H2AK119ub ChIP sequencing (ChIP-seq) peaks and their overlaps at transcription start sites of genes in indicated OCI-AML2 cells subjected to a 6-day treatment with DMSO or 1 μM VTP50469. (E) Averaged menin and H2AK119ub ChIP-seq signals over ±3 kb from transcription start sites of menin-specific target genes (left) and menin/H2AK119ub–shared target genes (right) in indicated OCI-AML2 cells subjected to a 6-day treatment with DMSO or 1 μM VTP50469. (F) Schematic illustrating the definition of type I and type II menin target genes. (G) Boxplots showing log2 ratio of menin signal to H2AK119ub signal within ±3 kb of the transcription start sites of type I and II menin target genes. (H) Boxplots illustrating the rescue indices of type I and II menin target genes. A rescue index value of 0 indicates no rescue effect, whereas a value of 1 denotes complete rescue. (I) Scatterplot showing a negative correlation between the rescue index and the signal balance of menin and H2AK119ub, represented by the log2-ratio of menin signal to H2AK119ub signal (top). Boxplots showing the log2FC in gene expression in the indicated OCI-AML2 cells compared with DMSO-treated sgLuc-expressing cells (bottom). Displayed are the top 10% of genes with the most balanced signals (left) and the top 10% of menin-dominant genes. (J) Menin and H2AK119ub ChIP-seq and RNA-seq profiles of representative type I and type II menin targets in indicated OCI-AML2 cells. (K) Schematic models depicting the mechanisms of transcriptional regulation by menin and PRC1.1-mediated H2AK119ub at type I and type II menin target genes. D, DMSO; RNA-seq, RNA sequencing; TSS, transcription start site; V, VTP50469.

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