SUMOylation orchestrates a metastable heterochromatin state on a MORC3-responsive element to silence IFNB1 at a distance [ChIP-seq]
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ABSTRACT:
PROVIDER: PRJNA1240230 | ENA |
REPOSITORIES: ENA
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Project description: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.
2025-07-17 | GSE292572 | GEO
Project description: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.
2025-07-17 | GSE292570 | GEO
Project description: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.
2025-07-17 | GSE292571 | GEO
Project description:SUMOylation orchestrates a metastable heterochromatin state on a MORC3-responsive element to silence IFNB1 at a distance
| PRJNA1240249 | ENA
Project description:SUMOylation orchestrates a metastable heterochromatin state on a MORC3-responsive element to silence IFNB1 at a distance [4C-seq]
| PRJNA1240231 | ENA
Project description:SUMOylation orchestrates a metastable heterochromatin state on a MORC3-responsive element to silence IFNB1 at a distance [RNA-seq]
| PRJNA1240234 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-07-16 | GSE292586 | GEO
Project description:We have identified MORC3 as a negative regulator of Type I Interferon (IFN), whose absence induces IFN and interferon-stimulated genes (ISGs). To study the global transcriptional effects of loss of MORC3, we deleted MORC3 in WT, IFNAR1–/– IFNAR2–/– and IFNB1–/– BLaER1 monocytes and performed RNA-seq.
2021-11-01 | GSE182755 | GEO
Project description:The SUMO pathway mainly functions to repress innate immunity in myeloid cells. Inactivating sumoylation triggers a strong, noncanonical, type I interferon (IFN1) response, amplified and coupled with inflammation upon stimulation. These findings transposed to pre-clinical models with the demonstration that sumoylation inhibitors activate antitumor immunity in an IFN1-dependent manner. Yet, how sumoylation represses immune signaling remains largely unknown. Here, we identified MORC3, a negative regulator of IFNB1, as the top SUMO2/3 substrate in myeloid cells. We show that, in monocytes, SUMO functions to repress basal IFNB1 in cis through a single long tandem repeat regulated by MORC3 [MORC3-regulated element (MRE)] that concentrates multiple motifs for the myeloid-enriched PU.1 factor. Inhibiting sumoylation induces a 3D genome reorganization nucleated from the MRE, which acquires both insulator and PU.1-activated enhancer activities, together with loss of H3.3 and H3K9me3 repressive marks and recruitment of PU.1. Paradoxically, MORC3, that interacts with PU.1, is massively recruited, yet unable to repress the MRE. Finally, we show that both sumoylation and MORC3 ATPase cycle are critical for MORC3 repressive activity. Our study thus uncovers an unconventional mechanism in which sumoylation, in concert with MORC3, orchestrates a metastable H3.3/H3K9me3 heterochromatin state on a multi-PU.1 binding platform to prevent an uncontrolled myeloid-specific immune response.
2025-08-16 | PXD061276 | Pride
Project description:Background: MORC proteins are involved in epigenetic gene silencing in a wide variety of eukaryotic organisms. Deletion of MORCs result in several developmental abnormalities and their dysregulation has been implicated in developmental disease and multiple cancers. Specifically, mutations of mammalian MORC3 have been associated with immune system defects, Down syndrome and human cancers such as bladder, uterine, stomach, and lung cancers, and diffuse large B cell lymphomas. While previous studies have shown that MORC3 binds to H3K4me3 in vitro and overlaps with H3K4me3 ChIP-seq peaks in mouse embryonic stem cells, the mechanism by which MORC3 regulates gene expression is unknown. Results: In this study, we find that MORC3 functions as an epigenetic silencer of endogenous retroviruses (ERVs) in mouse embryonic stem cells (mESCs). Loss of MORC3 results in upregulation of ERVs, specifically those belonging to the LTR class of retrotransposons. Using ChIP-seq, we measure the genome-wide localization of MORC3 in wild-type cells and find that MORC3 binds to ERVs suggesting its direct role in regulating ERV expression. Previous studies have shown that these ERVs are marked by repressive histone mark H3K9me3 which plays a key role in their silencing. Interestingly, we find that the levels of H3K9me3 do not change substantially upon the loss of MORC3 indicating that MORC3 possibly acts downstream of the TRIM28/SETDB1 complex that deposits H3K9me3 at these loci. Instead, we discover that loss of MORC3 results in increased chromatin accessibility at the ERVs suggesting that MORC3 silences ERVs by compacting DNA in mESCs. Conclusions: Our results reveal MORC3 as a novel regulator of ERV silencing in mouse embryonic stem cells. As early mammalian development is characterized by dynamic changes in ERV expression, the role of MORC3 in silencing ERVs is exciting and could potentially explain the abnormalities observed due to its misregulation during mammalian development.
2021-10-28 | GSE173913 | GEO