The MLL3/4 complexes and MiDAC co-regulate H4K20ac to control a specific gene expression program

Abstract

The mitotic deacetylase complex MiDAC has recently been shown to play a vital physiological role in embryonic development and neurite outgrowth. However, how MiDAC functionally intersects with other chromatin-modifying regulators is poorly understood. Here, we describe a physical interaction between the histone H3K27 demethylase UTX, a complex-specific subunit of the enhancer-associated MLL3/4 complexes, and MiDAC. We demonstrate that UTX bridges the association of the MLL3/4 complexes and MiDAC by interacting with ELMSAN1, a scaffolding subunit of MiDAC. Our data suggest that MiDAC constitutes a negative genome-wide regulator of H4K20ac, an activity which is counteracted by the MLL3/4 complexes. MiDAC and the MLL3/4 complexes co-localize at many genomic regions, which are enriched for H4K20ac and the enhancer marks H3K4me1, H3K4me2, and H3K27ac. We find that MiDAC antagonizes the recruitment of UTX and MLL4 and negatively regulates H4K20ac, and to a lesser extent H3K4me2 and H3K27ac, resulting in transcriptional attenuation of associated genes. In summary, our findings provide a paradigm how the opposing roles of chromatin-modifying components, such as MiDAC and the MLL3/4 complexes, balance the transcriptional output of specific gene expression programs.

Mitotic deacetylase complex (MiDAC) recognizes the HIV-1 core promoter to control Tat-activated transcription and latency

“…Furthermore, MiDAC has been implicated in gene expression during neurite outgrowth in mice [70] and the negative regulation of the H4K20ac histone modification [71]. Our findings that 1) DNTTIP1 directly recognizes TASHET DNA in vitro and in cellulo (Figs A role for DNTTIP1 in transcription was shown by placing DNTTIP1 consensus sites 5' of a minimal promoter where they produced increased reporter gene expression in response to DNTTIP1 overexpression [50].…”

“…Recent work has shown that MiDAC is essential for embryonic development in mice and forms a unique multivalent structure [69]. Furthermore, MiDAC has been implicated in gene expression during neurite outgrowth in mice [70] and the negative regulation of the H4K20ac histone modification [71]. Our findings that 1) DNTTIP1 directly recognizes TASHET DNA in vitro and in cellulo (Figs 3 & 4), 2) DNTTIP1, MIDEAS, and NAT10 are required for full HIV transcription (Figs 5 & 6), and 3) NAT10 associates with MIDEAS (Fig 2), together with published data showing that NAT10 interacts with HIV Tat [38, 39], support a model in which MiDAC is recruited to TASHET via the binding of its DNTTIP1 subunit (Fig 8).…”

Mitotic deacetylase complex (MiDAC) recognizes the HIV-1 core promoter to control activated viral gene expression

“…Recent work has shown that MiDAC is essential for embryonic development in mice and forms a unique multivalent structure [ 70 ]. Furthermore, MiDAC has been implicated in gene expression during neurite outgrowth in mice [ 71 ] and the negative regulation of the H4K20ac histone modification [ 72 ]. Our findings that 1) DNTTIP1 directly recognizes TASHET DNA in vitro and in cellulo (Figs 3 and 4 ), 2) DNTTIP1, MIDEAS, and NAT10 are required for full HIV transcription (Figs 5 and 6 ), and 3) NAT10 associates with MIDEAS ( Fig 2 ), together with published data showing that NAT10 interacts with HIV Tat [ 38 , 39 ], support a model in which MiDAC is recruited to TASHET via the binding of its DNTTIP1 subunit ( Fig 8 ).…”

Alternative mRNA Splicing Controls the Functions of the Histone H3K27 Demethylase UTX/KDM6A

“…PR-DUB binding is compromised by cancer mutations in MLL3 and could be partially balanced by UTX in an experimental setting [ 11 ]. Recent studies have also demonstrated the interaction of UTX with the mitotic deacetylase complex (MiDAC) [ 12 , 13 ]. Interestingly, UTX escapes X inactivation in females, which is compensated for in males by the chromosome Y encoding the UTY ortholog (also referred to as KDM6C) [ 14 , 15 ].…”