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SUMOylation orchestrates a metastable heterochromatin state on a MORC3-responsive element to silence IFNB1 at a distance [ChIP-seq]

ABSTRACT: Despite the pleiotropic role of SUMOylation, this pathway mainly functions to repress innate immunity in myeloid cells. Inactivating SUMOylation triggers a potent basal type I interferon (IFN1) response, amplified and coupled with an inflammatory response upon stimulation. These findings transposed to pre-clinical models with the demonstration that SUMOylation inhibitors (SUMOi) activate antitumor immunity in an IFN1-dependent manner. Yet, how SUMOylation represses immune signaling remains largely unknown. We identified murine MORC3, a critical transcriptional repressor of the IFNB1 gene, as the top SUMO2/3 substrate in myeloid cells. We show that, in human monocytes, SUMO functions to repress basal IFNB1 in cis through an atypical/repeated MORC3-regulated element (MRE) concentrating/homing multiple PU.1 binding motifs. Inhibiting SUMOylation induces a 3D genome reorganization centered on the MRE, which, in turn, acquires both insulator and PU.1-driven enhancer activities, together with loss of H3.3 and H3K9me3 repressive marks and increased PU-1 binding. Paradoxically, MORC3, that binds PU.1, is massively recruited, yet unable to repress the MRE. Finally, we show that both MORC3 ATPase cycle and SUMOylation are critical for full MORC3 repressive activity. Our study identifies an unconventional mechanism in which SUMO, in concert with MORC3, orchestrates a metastable H3.3/H3K9me3 heterochromatin state on a multi-PU.1 binding platform element to shutdown unscheduled myeloid-specific IFN1 response.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE292571 | GEO | 2025/07/17

REPOSITORIES: GEO

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Project description:Endogenous retroviruses (ERVs) comprise a significant portion of mammalian genomes. Although specific ERV loci feature regulatory roles for host gene expression, most ERV integrations are transcriptionally repressed by Setdb1 mediated H3K9me3 and DNA methylation. However, the protein network which regulates the deposition of these chromatin modifications is still incompletely understood. Here, we performed a genome-wide sgRNA screen for genes involved in ERV silencing and identified the GHKL ATPase protein Morc3 as a top-scoring hit. Morc3 knock-out cells display de-repression, reduced H3K9me3, and increased chromatin accessibility of distinct ERV families. We found that the Morc3 ATPase cycle and Morc3 SUMOylation are important for ERV chromatin regulation. Proteomic analysis revealed that Morc3 mutant proteins fail to interact with the histone H3.3 chaperone Daxx. This interaction depends on Morc3 SUMOylation and Daxx SUMO binding. Notably, in Morc3 ko cells, we observed strongly reduced histone H3.3 on Morc3 binding sites. Thus, our data demonstrate Morc3 as a critical regulator of Daxx-mediated histone H3.3 incorporation to ERV regions. This dataset comprises several experiments addressing different questions: 1. ChIP-MS experiment to determine the protein interaction context of Morc3 using a Morc3-3xFLAG knock-in ES cell line compared to wild type ES cells (Experiment 20200408). 2. ChIP-MS experiments to investigate changes in the protein interaction context of the Morc3 mutant rescue cell lines. Comparison of Morc3 knock-out cell lines with re-expression of Morc3-CW-3xFLAG mutant (Ref. #3111), Morc3-ATP-binding-3xFLAG and Morc3-SUMOylation-3xFLAG mutants (Ref. #3635), and Morc3-deltaN-3xFLAG mutant (Ref. #5174) compared to wt Morc3-3XFLAG rescue. 3. ChIP-MS experiment to determine if the interaction between Morc3 and Daxx is mediated through this C-terminal SIM, comparing Daxx knock-out cell lines with re-expression of wild type 3xFLAG-Daxx protein or 3xFLAG-Daxx ∆SIM, which lacks the C-terminal SIM domain. (Ref. #3301)

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SUMOylation orchestrates a metastable heterochromatin state on a MORC3-responsive element to silence IFNB1 at a distance [ChIP-seq]

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