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De novo mutations in the MiDAC HDAC complex cause a neurodevelopmental 2 syndrome resulting from increased deacetylase activity [RNA-seq]

ABSTRACT: MIDEAS is a scaffold protein that, together with DNTTIP1, mediates assembly of the MiDAC histone deacetylase complex. Mice lacking MiDAC die before birth suggesting a key developmental function. Here, we report two unrelated individuals, with a multisystem disorder characterized by delayed speech development, joint contractures, dysmorphic features and dysmotility of the gut. Both individuals have the same de novo heterozygous missense variant in MIDEAS (p.Tyr654Ser). A cryoEM structure of the MiDAC complex reveals that this amino acid is located in a conserved auto-inhibitory loop that covers the active site of the deacetylase enzyme. We suggest that the variant results in loop displacement leading to elevated deacetylase activity. In support, we observe reciprocal gene expression changes in patient fibroblasts compared with a cell line following rapid MiDAC degradation. Our results establish MIDEAS as a dominant monogenic disease gene and that hyperactivity of the MiDAC complex results in a characteristic multisystem disorder.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE297959 | GEO | 2025/10/13

REPOSITORIES: GEO

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De novo mutations in the MiDAC HDAC complex cause a neurodevelopmental 2 syndrome resulting from increased deacetylase activity [qPRO-seq]

Project description:MIDEAS is a scaffold protein that, together with DNTTIP1, mediates assembly of the MiDAC histone deacetylase complex. Mice lacking MiDAC die before birth suggesting a key developmental function. Here, we report two unrelated individuals, with a multisystem disorder characterised by delayed speech development, joint contractures, dysmorphic features and dysmotility of the gut. Both individuals have the same de novo heterozygous missense variant in MIDEAS (p.Tyr654Ser). A cryoEM structure of the MiDAC complex reveals that this amino acid is located in a conserved auto-inhibitory loop that covers the active site of the deacetylase enzyme. We suggest that the variant results in loop displacement leading to elevated deacetylase activity. In support, we observe reciprocal gene expression changes in patient fibroblasts compared with a cell line following rapid MiDAC degradation. Our results establish MIDEAS as a dominant monogenic disease gene and that hyperactivity of the MiDAC complex results in a characteristic multisystem disorder.

2025-10-13 | GSE297958 | GEO

The interdependency between MiDAC complex and MLL3/4 complexes

Project description:Enhancers play a pivotal role in gene transcriptional regulation in response to developmental cues. Active enhancers are marked by H3K4me1/2 and H3K27ac, while poised enhancers are marked by H3K27me3 instead of H3K27ac in addition to H3K4me1/2. How these histone modifications and/or other histone modification(s) at enhancers are regulated remains not fully understood. Through immunoprecipitation followed by mass spectrometry of UTX, a specific subunit of the enhancer associated COMPASS complex: MLL3/4, we identified DNTTIP1 and ELMSAN1, which are scaffolds of the mitotic deacetylase complex (MiDAC), as new UTX interactors. Our biochemistry data shows that UTX-ELMSAN1 is the interface between MiDAC and MLL3/4 complexes. The loss of MiDAC causes genome wide increase of H4K20ac, suggesting H4K20ac is a MiDAC substrate in vivo. H4K20ac is genome-wide co-localized with H3K4me1/2, H3K27ac, UTX, and MLL4, suggesting it is located at active enhancers. Genome-wide increased occupancy of UTX and MLL4 is observed at Dnttip1 knockout mES cells, which means under normal conditions MiDAC may repress MLL3/4-UTX’s genomic localization. However, we observe an increase of H3K4me2 but not H3K4me1 at those UTX & MLL4 increased loci. In MLL3/4 double knockout mES cells, Dnttip1 is reduced genome-wide, which however does not lead to a genome-wide increase of H4K20ac, but a genome-wide loss of it. At either H4K20ac or Dnttip1 reduction loci, we observe an increase of H3K27me3, suggesting the formation of repressed chromatin state which may suppress the increase of H4K20ac at Dnttip1 reduced loci. Our study for the first time reveals the functional intersection between MiDAC and MLL3/4 complexes.

2022-06-27 | GSE190323 | GEO

The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression to control neurite outgrowth [ChIP-Seq]

Project description:Cell type diversity during neuro-ectodermal (NE) differentiation is achieved through selective activation and silencing of neurodevelopmental genes. Here, we show a key role for the histone deacetylase complex MiDAC during neuronal differentiation of mouse embryonic stem cells (mESCs) into NE. We demonstrate that MiDAC functions as a modulator of a neurodevelopmental gene expression program and binds to important regulators of neurite outgrowth. MiDAC mediates the removal of H4K20ac on the promoters and enhancers of pro-neural genes such as the axon guidance ligands Slit3 and Ntn1 while in parallel reducing H3K27ac on promoter-proximal and -distal elements of negative regulators of neurogenesis thereby upregulating and inhibiting gene expression, respectively. Furthermore, neurite outgrowth defects in MiDAC KO neurons can be rescued by restoring Slit3/Robo3-Ntn1/Unc5b signaling. Taken together, our work suggests a crucial role for MiDAC in regulating the secretome of the Slit3/Robo3-Ntn1/Unc5b signaling axes to ensure the proper integrity of neurite development.

2020-04-08 | GSE131061 | GEO

The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression to control neurite outgrowth [RNA-Seq]

2020-04-08 | GSE131060 | GEO

ChIP-Seq mapping of H2AK5ac, H2AK9ac, DNTTIP1, MIDEAS, and LIG4 at AsiSI-induced DNA double-strand breaks in control or MiDAC-deficient cells

Project description:To test whether MiDAC-promoted H2AK5/K9 deacetylation is implicated in DSB response, we took advantage of an improved DSB-induced via AsiSI (AiDIvA) system, in which the endonuclease restriction enzyme AsiSI is fused to the estrogen receptor (ER) hormone-binding domain and its nuclear expression in HeLa cells is controlled by doxycycline and 4-hydroxy tamoxifen (4-OHT). The precise distribution of gH2AX, H2AK5ac, H2AK9ac, FLAG-DNTTIP1, FLAG-MIDEAS, and LIG4 at AsiSI-induced DNA double-strand breaks was determined by chromatin immunoprecipitation coupled high throughput sequencing (ChIP-seq). ChIP signals from ER-AsiSI-expressing AiDIvA cells (DSB group) were normalized to ER-expressing control cells (Ctrl group).

2024-02-16 | GSE235845 | GEO

The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression to control neurite outgrowth

Project description:The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression to control neurite outgrowth

| PRJNA542528 | ENA

The interdependency between MiDAC complex and MLL3/4 complexes

Project description:The interdependency between MiDAC complex and MLL3/4 complexes

| PRJNA786640 | ENA

The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression to control neurite outgrowth [ChIP-Seq]

Project description:The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression to control neurite outgrowth [ChIP-Seq]

| PRJNA542516 | ENA

The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression to control neurite outgrowth [RNA-Seq]

Project description:The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression to control neurite outgrowth [RNA-Seq]

| PRJNA542515 | ENA

Embryonic day 13.5 mRNA profiles for wildtype and MIDEAS and DNTTIP1 knockout MEFs

Project description:Objective: Perform deep sequencing on mouse embryonic fibroblasts from e13.5 embryos with wildtype, MIDEAS-/- and DNTTIP1-/- genotypes to provide insights into observed embryonic lethality with associated haemolytic anaemia and heart defects. Method: Heterozygous mates of MIDEAS or DNTTIP1 set up and pregnant females culled at e13.5. MEFs were created from embryos and cultured for 4-6 passages before total RNA extraction and deep sequencing (novogene) to obtain mRNA pofiles. FastQ files processed using TRIMGALORE!, STAR, Picards remove duplicates and SAM Tools. R was used for DESeq2 analysis to find differentially regulated genes Results: A large number of both up and down regulated genes were found for both MIDEAS and DNTTIP1 knockout MEFs compared to wildtype. Of these a significant amount were common to both knockouts suggesting a role in the same complex and shared gene targets. A number of these transcripts were associated with angiogenesis and haematopoiesis as well as neual development. Conclusion: Whilst further biological experiments are required to confirm reason for haemolytic anaemia present in knockout embryos there is a strong indication this could be caused by changes in gene regulation cause by the loss of the MIDAC compex

2020-05-26 | GSE144748 | GEO

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