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FIGURE 1 from Proteasome Inhibition Reprograms Chromatin Landscape in Breast Cancer

figure

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

Proteasome inhibition reprograms accessible chromatin. A, Heat maps showing differential (MG treated minus untreated) signal for DNA accessibility (ATAC, nucleosome-free reads <100 bp), H3K27ac (K27ac), H3K4me1 (Kme1), and H3K4me3 (K4me3) at DOCRs that increase (GAIN) accessibility after 24H treatment compared with untreated. B, Heat maps as in A at DOCRs that decrease (LOST) accessibility. Signal spans ±1 kb from the center of the defined DOCR regions and is ranked on the basis of the degree of change in accessibility, where regions at the top have the most change in accessibility. The color scale shows an increase (red) or decrease (blue) in differential signal. Side by side heat maps show differential signal at the 4H and 24H time points. DOCRs are split by genomic category into PROMOTER, GENIC, and INTERGENIC. N is the number of DOCRs in each genomic category. C, Metaplots for ATAC signal and ChIP-seq binding signals of K27ac, K4me1, and K4me3 at GAIN DOCRs. D, Metaplots as in C, LOST DOCRs. Signal includes the untreated state (0) and after 4H and 24H of treatment. Line color density reflects treatment conditions [light (0) to darkest 24H)]. E, Pie charts showing the proportion of DOCRs assigned to various chromatin states using Epilogos https://epilogos.altius.org/. N is the number of DOCRs 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.