Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours

Abstract

Mutations and expression changes of epigenetic modifiers are pervasive in human tumours, making epigenetic factors attractive anti-tumour targets. The open-versus-closed chromatin state within cancer cells-of-origin correlates with the uneven distribution of mutations. However, the long-term effect on mutability of targeting epigenetic modifiers in cancer patients is unclear. Here we show that increasing chromatin accessibility by deleting histone H3 lysine 9 (H3K9) methyltransferase G9a in murine epidermis does not alter the singlenucleotide variants (SNVs) burden or global genomic distribution in chemical mutagen-induced squamous tumours. G9a-depleted tumours developed after a prolonged latency compared to their wild-type counterparts but were more aggressive and had an expanded cancer progenitor pool, pronounced genomic instability and frequent loss-of-function p53 mutations. Thus, we call for caution when assessing long-term therapeutic benefits of chromatin modifier inhibitors, which may promote more aggressive disease.

Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis

“…Loss of heterochromatin reader protein HP1 causes chromosome segregation and is associated with cancer progression 10 . Depletion of a histone methyltransferase, G9a, results in the development of more aggressive tumors in mice that are genomically unstable 11 . At the genomic level, satellite repeats (enriched with H3K9me3) are required for heterochromatin formation and accurate chromosome segregation 12 .…”

“…What is the characteristic molecular-scale chromatin abnormality in cancer cells? Although coarse aggregation of heterochromatin has been a well-documented microscopic feature diagnostic of many cancers 2 , numerous biological studies reported the loss of heterochromatin-associated proteins and post-translational marks in cancer cells which cannot explain the aggregated heterochromatin structure 5,7,11 . Aberrant chromatin structure is a characteristic of cancer cells, but what happens in early carcinogenesis when cells still appear normal prior to tumor formation?…”

Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis

“…Our observed higher-order heterochromatin decompaction is largely in line with previous functional studies of dysregulated heterochromatin in cancer. The loss of heterochromatin proteins or post-translational marks (e.g., H3K9me3, H3K9me2, and HP1) has been widely reported in cancer cells and its functional consequences of impairing genomic stability, changing transcriptional programs, and promoting tumorigenesis and cancer progression (Avgustinova et al, 2018;Carone and Lawrence, 2013;Dialynas et al, 2008;Janssen et al, 2018;Peters et al, 2001;Reddy and Feinberg, 2013;Timp and Feinberg, 2013). While few studies have examined dysregulated heterochromatin in precursor lesions, our study underlines the importance of disrupting the highly compact heterochromatin structure as an initial barrier for malignant transformation.…”

“…Loss of heterochromatin reader protein HP1 causes chromosome segregation and is associated with cancer progression (Dialynas et al, 2008). Depletion of a chromatin modifier, G9a, results in the development of tumors in mice that are more aggressive tumors and genomically unstable (Avgustinova et al, 2018). At the genomic level, satellite repeats (enriched with H3K9me3) are required for heterochromatin formation and accurate chromosome segregation (Saksouk et al, 2015).…”

“…What is the characteristic molecular-scale chromatin abnormality in cancer cells? Coarse aggregation of heterochromatin has been a well-documented microscopic feature diagnostic of many cancers (Zink et al, 2004), but numerous biological studies reported the loss of heterochromatinassociated proteins and post-translational marks in cancer cells which cannot explain the aggregated heterochromatin structure (Avgustinova et al, 2018;Janssen et al, 2018;Peters et al, 2001). Aberrant chromatin structure is a characteristic of cancer cells when normal cells have already turned into tumor, but what happens in early carcinogenesis when cells still appear normal prior to tumor formation?…”