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FIGURE 3 from Proteasome Inhibition Reprograms Chromatin Landscape in Breast Cancer

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posted on 2024-04-16, 14:20 authored by H. Karimi Kinyamu, Brian D. Bennett, James M. Ward, Trevor K. Archer

Proteasome inhibition exhibits specific effects on divergent transcription. A, Heat maps showing differential signal for start RNA, DNA accessibility (ATAC), RNAPII (Ser5P), and active histone marks (K27ac, K122ac, K4me1, K4me3) at genic TSSs with divergent transcription that overlap GAIN DOCRs. B, Heat maps as in A, overlap LOST DOCRs. Signal spans ±500 bases from the TSSs and is ranked by distance between sense and antisense TSS pairs, where TSSs at the top have the shortest distance between pairs. TSSs are split by category into Promoter Upstream Transcripts (PROMPT) and Bidirectional (head-to-head) TSS pairs. N is the number of TSS pairs in each category. C, Scatter plot showing gene expression changes of bidirectional (head-to-head) TSS pairs. TSS pairs are colored by gene class, where each TSS in the pair is either protein coding (PC) or non-coding (NC). D, Violin plot showing gene expression changes of genic TSSs associated with promoter upstream transcript (PROMPT) category. Significantly different genes (FDR ≤ 0.05, log₂FC±1) are colored red (upregulated) and blue (downregulated). Gold labeled are non-coding genes. E, Heat maps showing differential signal of features in A at non-genic TSSs that overlap GAIN DOCRs. F, Heat maps showing differential signal of features in A at non-genic TSSs that overlap LOST DOCRs. TSSs are split by genomic category into gene body and intergenic. G, Violin plot showing gene expression changes of genes closest to non-genic TSSs, which are split by genomic category into gene body and intergenic. N is the number of TSS pairs in each category.

Funding

HHS | NIH | National Institute of Environmental Health Sciences (NIEHS)

History

ARTICLE ABSTRACT

The 26S proteasome is the major protein degradation machinery in cells. Cancer cells use the proteasome to modulate gene expression networks that promote tumor growth. Proteasome inhibitors have emerged as effective cancer therapeutics, but how they work mechanistically remains unclear. Here, using integrative genomic analysis, we discovered unexpected reprogramming of the chromatin landscape and RNA polymerase II (RNAPII) transcription initiation in breast cancer cells treated with the proteasome inhibitor MG132. The cells acquired dynamic changes in chromatin accessibility at specific genomic loci termed differentially open chromatin regions (DOCR). DOCRs with decreased accessibility were promoter proximal and exhibited unique chromatin architecture associated with divergent RNAPII transcription. Conversely, DOCRs with increased accessibility were primarily distal to transcription start sites and enriched in oncogenic superenhancers predominantly accessible in non-basal breast tumor subtypes. These findings describe the mechanisms by which the proteasome modulates the expression of gene networks intrinsic to breast cancer biology. Our study provides a strong basis for understanding the mechanisms by which proteasome inhibitors exert anticancer effects. We find open chromatin regions that change during proteasome inhibition, are typically accessible in non-basal breast cancers.