Histone demethylase enzymes KDM5A and KDM5B modulate immune response by suppressing transcription of endogenous retroviral elements

Epigenetic factors, including lysine-specific demethylases such as the KDM5 paralogs KDM5A and KDM5B have been implicated in cancer and the regulation of immune responses. Here, we performed a comprehensive multiomic study in cells lacking KDM5A or KDM5B to map changes in transcriptional regulation and chromatin organization. RNA-seq analysis revealed a significant decrease in the expression of Kruppel-associated box containing zinc finger (KRAB-ZNF) genes in KDM5A or KDM5B knockout cell lines, which was accompanied by changes ATAC-seq and H3K4me3 ChIP-seq. Pharmacological inhibition of KDM5A and KDM5B catalytic activity with a pan-KDM5 inhibitor, CPI-455, did not significantly change KRAB-ZNF expression, raising the possibility that regulation of KRAB-ZNF expression does not require KDM5A and KDM5B demethylase activity. KRAB-ZNF are recognized suppressors of the transcription of endogenous retroviruses (ERVs) and HAP1 cells with KDM5A or KDM5B gene inactivation showed elevated ERV expression, increased dsRNA levels and elevated levels of immune response genes. Acute degradation of KDM5A using a dTAG system in HAP1 cells led to increased ERV expression, demonstrating that de-repression of ERV genes occurs rapidly after loss of KDM5A. Co-immunoprecipitation of KDM5A revealed an interaction with the Nucleosome Remodeling and Deacetylase (NuRD) complex suggesting that KDM5A and NuRD may act together to regulate the expression of ERVs through KRAB-ZNFs. These findings reveal roles of KDM5A and KDM5B in modulating ERV expression and underscore the therapeutic potential of using degraders of KDM5A and KDM5B to modulate tumor immune responses. Author SummaryThe histone demethylases KDM5A and KDM5B are transcriptional repressors that play an important role in cancer and immune response, making them attractive drug targets. Unfortunately, small molecule inhibitors, including CPI-455, that block KDM5A and KDM5B enzymatic activity, have shown only limited effectiveness at suppressing cancer cell viability as single agents in vitro. In this study we undertook a multi-omics approach to map transcriptional and chromatin changes in KDM5A and KDM5B deficient cells compared to those treated with CPI-455. The datasets revealed that KDM5A and KDM5B modulate the expression of KRAB-ZNF genes and that loss of either gene was associated with increased expression of ERV genes and upregulation of immune response markers. Surprisingly, pharmacological inhibition of these enzymes did not phenocopy genetic ablation. In contrast, acute degradation of KDM5A using a dTAG system caused an increase in ERV expression, providing evidence that this immune modulation is independent of demethylase activity. Together with the limited success of small molecule inhibitors, our data provide strong rationale for the development of KDM5A and KDM5B degraders to modulate tumor immune responses.