Identification of Two Distinct Classes of the Human INO80 Complex Genome-Wide

Abstract

Chromatin remodeling and histone modifying enzymes play a critical role in shaping the regulatory output of a cell. Although much is known about these classes of proteins, identifying the mechanisms by which they coordinate gene expression programs remains an exciting topic of investigation. One factor that may contribute to the targeting and activity of chromatin regulators is local chromatin landscape. We leveraged genomic approaches and publically-available datasets to characterize the chromatin landscape at targets of the human INO80 chromatin remodeling complex (INO80-C). Our data revealed two classes of INO80-C targets with distinct chromatin signatures. The predominant INO80-C class was enriched for open chromatin, H3K27ac, and representative subunits from each of the three INO80-C modules (RUVBL1, RUVBL2, MCRS1, YY1). We named this class Canonical INO80. Notably, we identified an unexpected class of INO80-C targets that contained only the INO80 ATPase and harbored a repressive chromatin signature characterized by inaccessible chromatin, H3K27me3, and the methyltransferase EZH2. We named this class Non-Canonical INO80 (NC-INO80). Biochemical approaches indicated that INO80-C and the H3K27 acetyltransferase P300 physically interact, suggesting INO80-C and P300 may jointly coordinate chromatin accessibility at Canonical INO80 sites. No interaction was detected between INO80-C and EZH2, indicating INO80-C and EZH2 may engage in a separate form of regulatory crosstalk at NC-INO80 targets. Our data indicate that INO80-C is more compositionally heterogenous at its genomic targets than anticipated. Moreover, our data suggest there is an important link between INO80-C and histone modifying enzymes that may have consequences in developmental and pathological contexts.

INO80 promotes H2A.Z occupancy to regulate cell fate transition in pluripotent stem cells

“…2b), suggesting that it may play an important role in their regulation. This is consistent with the recent discovery that human INO80 occupies both active and repressive chromatin domains (38).…”

Symmetric neural progenitor divisions require chromatin-mediated homologous recombination DNA repair by Ino80

“…In addition to DNA repair, we find a gene regulatory role for Ino80 in YY1-associated transcription. Previous studies have shown that INO80 and YY1 interact 44 , bind open chromatin 15 , and mediate transcriptional activation 17 . This role is compromised in Ino80 cKO-E, which is characterized by downregulation of YY1-associated genes.…”

Linc‐MYHconfiguresINO80 to regulate muscle stem cell numbers and skeletal muscle hypertrophy

“…We therefore concluded that linc‐MYH specifically controls the function of INO80 in the regulation of MuSC abundance and proliferation but not in DNA repair. The data also suggest that the linc‐MYH‐dependent function of INO80 might rely on YY1, which is a known interactor of the INO80 complex (Cai et al , 2007; Wu et al , 2007; Chen et al , 2011; Runge et al , 2018).…”