ARID1A recruits TRIM28 for the essential remodeling of heterochromatin independent of SWI/SNF.
ARID1A functions as a vital tumor suppressor whose activity usually depends on the SWI/SNF chromatin remodeling complex. ARID1A is highly mutated across human cancers, and its deficiency has been found to promote immunogenicity through impaired mismatch repair and elevated tumor mutation burden. However, little is known about the SWI/SNF-independent function of ARID1A and the subsequent consequences. Here, we report a novel mechanism of action that ARID1A maintains heterochromatin integrity and silences endogenous satellite/retroelements, independent of SWI/SNF and microsatellite instability. Mechanistically, ARID1A recruits TRIM28 to keep the rigidity of heterochromatin. Loss of ARID1A displaces SETDB1 from TRIM28-contraining heterochromatin complex to induce the derepression of H3K9me3 at endogenous satellite/retroelement regions. The unleashed satellites and retroelements resulting from impaired ARID1A-TRIM28 interaction trigger type-I interferon immune responses, promoting tumor progression and sensitivity to PD1 blockade through both RNA- and DNA-sensing pathways. Our results shed light on the SWI/SNF-independent function of ARID1A to necessarily maintain heterochromatin integrity and safeguard the immunogenicity, potentiating the disruption of ARID1A-TRIM28 interaction as a strategy to convert ARID1A-wildtype tumors into hot to strengthen the therapeutic efficacies. Overall design: ATAC-seq of control (shCtrl; n=3) and ARID1A-loss (shARID1A; n=3) HCT116 cells.