Abstract
BackgroundStudies indicate that the 19S proteasome contributes to chromatin reorganization, independent of the role the proteasome plays in protein degradation. We have previously shown that components of the 19S proteasome are crucial for regulating inducible histone activation events in mammalian cells. The 19S ATPase Sug1 binds to histone-remodeling enzymes, and in the absence of Sug1, a subset of activating epigenetic modifications including histone H3 acetylation, H3 lysine 4 trimethylation and H3 arginine 17 dimethylation are inhibited at cytokine-inducible major histocompatibilty complex (MHC)-II and class II transactivator (CIITA) promoters, implicating Sug1 in events required to initiate mammalian transcription.ResultsOur previous studies indicate that H3 lysine 4 trimethylation at cytokine-inducible MHC-II and CIITA promoters is dependent on proteolytic-independent functions of 19S ATPases. In this report, we show that multiple common subunits of the mixed lineage leukemia (MLL)/complex of proteins associated with Set I (COMPASS) complexes bind to the inducible MHC-II and CIITA promoters; that overexpressing a single common MLL/COMPASS subunit significantly enhances promoter activity and MHC-II HLA-DRA expression; and that these common subunits are important for H3 lysine 4 trimethylation at MHC-II and CIITA promoters. In addition, we show that H3 lysine 27 trimethylation, which is inversely correlated with H3 lysine 4 trimethylation, is significantly elevated in the presence of diminished 19S ATPase Sug1.ConclusionTaken together, these experiments suggest that the 19S proteasome plays a crucial role in the initial reorganization of events enabling the relaxation of the repressive chromatin structure surrounding inducible promoters.
Highlights
Studies indicate that the 19S proteasome contributes to chromatin reorganization, independent of the role the proteasome plays in protein degradation
Common mixed lineage leukemia (MLL)/complex of proteins associated with Set I (COMPASS) subunits associate with cytokine-inducible promoters H3K4me3 is mediated by histone methyltransferase (HMTase) enzymes, which are typically recruited to DNA as part of a larger complex of proteins MLL/ COMPASS [7,8,10,35]
We previously showed that the 19S ATPase Sug1 positively regulates H3K4me3 at the major histocompatibilty complex (MHC)-II proximal promoter and at class II transactivator (CIITA) promoter IV (pIV), potentially by stabilizing the association of common MLL/ COMPASS subunits [36]
Summary
Studies indicate that the 19S proteasome contributes to chromatin reorganization, independent of the role the proteasome plays in protein degradation. The 19S ATPase Sug binds to histone-remodeling enzymes, and in the absence of Sug, a subset of activating epigenetic modifications including histone H3 acetylation, H3 lysine 4 trimethylation and H3 arginine 17 dimethylation are inhibited at cytokine-inducible major histocompatibilty complex (MHC)-II and class II transactivator (CIITA) promoters, implicating Sug in events required to initiate mammalian transcription. Di- or trimethylation (hypermethylation) of histone H3 at lysine 4 (H3K4) is found at actively transcribed genes [1,2,3,4,5], is functionally linked to activating acetylation events at promoters [6], and is mediated by the mixed lineage leukemia (MLL)/complex of proteins associated with Set I (COMPASS)-like complexes [7,8]. Much is known about the requirement of transcription factors at these cytokine-inducible promoters, considerably less is understood about the coordination of the histone modifying events that allow these promoters to switch from a semi-poised state to a fully open, transcription-accessible structure
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