Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development

Avgustinova, Alexandra; Laudanna, Carmelo; Pascual-García, Mónica; Rovira, Quirze; Djurec, Magdolna; Castellanos, Andrés; Urdiroz-Urricelqui, Uxue; Marchese, Domenica; Prats, Neus; Keymeulen, Alexandra Van; Heyn, Holger; Vaquerizas, Juan M.; Benitah, Salvador Aznar

doi:10.1016/j.stem.2021.04.030

Cited by 11 publications

(5 citation statements)

References 68 publications

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“…Since H3K9me2 is also known to repress repeated sequences (25,26), we analyzed CUT&Tag data by considering all mapping reads, either unique and multiple, that mapped to the genome without mismatch, and we randomly assigned them at one of their best possible positions in the genome (11). This analysis identified a pronounced enrichment of the H3K9me2 mark at TE relative to genes in patients, with 13,364 TEs among H3K9me2-bound peaks in CMML cells, compared to 255 in control cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting Heterochromatin Eliminates Malignant Hematopoietic Stem and Progenitor Cells in Chronic Myelomonocytic Leukemia Through Reactivation of Retroelements and Innate Immune pathways

Hidaoui,

Chelbie,

Bohm

et al. 2024

Preprint

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Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy affecting the elderly, for which therapeutic options are limited. DNA hypomethylating agents (HMAs) provide transient responses, failing to eradicate the malignant clone. Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization, evidenced by alterations in histone marks H3K9me2 and H3K9me3. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In solid cancers, the antitumor efficacy of HMAs involves the derepression of TEs, mimicking a state of viral infection. In this study, we demonstrate a significant disorganization of heterochromatin in CMML HSCs and progenitors (HSPCs) characterized by an increase in the repressive mark H3K9me2, mainly at the level of TEs, and a repression of immune and age-associated transcripts. Combining HMAs with G9A/GLP H3K9me2 methyltransferase inhibitors reactivates these pathways, selectively targeting mutated cells while preserving wild-type HSCs, thus offering new therapeutic avenues for this severe myeloid malignancy.

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Section: Resultsmentioning

confidence: 99%

Targeting Heterochromatin Eliminates Malignant Hematopoietic Stem and Progenitor Cells in Chronic Myelomonocytic Leukemia Through Reactivation of Retroelements and Innate Immune pathways

Hidaoui,

Chelbie,

Bohm

et al. 2024

Preprint

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show abstract

“…S 6 B, C) [ 39 ]. Other authors [ 6 , 40 ] have associated the genomic redistribution of H3K9me3, and a massive decreased level at heterochromatin repressive regions, with a rapid de-silencing of transposable elements (TEs) that can induce an immune response or, potentially, a genomic instability impacting on cancer cell survival. In accordance with these observations, we found that 91.79% ( n = 358) of TE families affected by maltonis treatment are upregulated, while only 8.2% ( n = 32) are downregulated (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Small molecule-induced epigenomic reprogramming of APL blasts leading to antiviral-like response and c-MYC downregulation

et al. 2022

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Acute promyelocytic leukemia (APL) is an aggressive subtype of acute myeloid leukemia (AML) in which the PML/RARα fusion protein exerts oncogenic activities by recruiting repressive complexes to the promoter of specific target genes. Other epigenetic perturbations, as alterations of histone H3 lysine 9 trimethylation (H3K9me3), have been frequently found in AMLs and are associated with leukemogenesis and leukemia progression. Here, we characterized the epigenomic effects of maltonis, a novel maltol-derived molecule, in APL cells. We demonstrate that maltonis treatments induce a profound remodulation of the histone code, reducing global H3K9me3 signal and modulating other histone post-translational modifications. Transcriptomic and epigenomic analyses revealed that maltonis exposure induces changes of genes expression associated with a genomic redistribution of histone H3 lysine 4 trimethylation (H3K4me3) and lysine 27 acetylation (H3K27ac). Upregulation of interferon alpha and gamma response and downregulation of c-MYC target genes, in function of c-MYC reduced expression (monitored in all the hematopoietic neoplasms tested), represent the most significant modulated pathways. These data demonstrate the ability of maltonis to epigenetically reprogram the gene expression profile of APL cells, inducing an intriguing antiviral-like response, concomitantly with the downregulation of c-MYC-related pathways, thus making it an attractive candidate for antileukemic therapy.

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“…HERVs are mainly localized in heterochromatin and repressed by epigenetic silencing at steady state 24,25 . Previous studies have shown that DNA hypomethylation, leading to ISGs overexpression in SLE patients, contributed to SLE pathogenesis 26 .…”

Section: Screening and Identi Cation Of The Differentially Expressed ...mentioning

confidence: 99%

Endogenous retrovirus promotes the aberrant T cell differentiation in systemic lupus erythematosus via RIG-I pathway

Zhao,

Min,

et al. 2024

Preprint

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The dysregulated differentiation of T lymphocyte play an important role in systemic lupus erythematosus (SLE). However, the underlying mechanism remains unclear. Here, we showed that many transcripts derived from human endogenous retroviruses (HERVs) were highly expressed in CD4+ T cells from SLE patients due to DNA hypomethylation, some of which were characterized by double strand RNAs (dsRNAs). Excessive dsRNAs promoted Th1/Th17 differentiation and inhibited Treg cell differentiation via the activation of dsRNA sensor retinoic acid-inducible gene I (RIG-I). And T cell-specific ablation of RIG-I alleviated disease progression in experimental autoimmune encephalomyelitis (EAE) mice model and lupus-like mice model. Importantly, we demonstrated that dsRNA-activated RIG-I protein bind lactate dehydrogenase A (LDHA) and regulate histone lysine 18 lactylation (H3K18Lac) and acetylation (H3K18Ac) modifications in T cell differentiation via changing lactate level. Collectively, our findings uncover a novel role and mechanism of HERVs and RIG-I in regulating the aberrant differentiation of T cells in SLE patients.

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Repression of endogenous retroviruses prevents antiviral immune response and is required for mammary gland development

Cited by 11 publications

References 68 publications

Targeting Heterochromatin Eliminates Malignant Hematopoietic Stem and Progenitor Cells in Chronic Myelomonocytic Leukemia Through Reactivation of Retroelements and Innate Immune pathways

Targeting Heterochromatin Eliminates Malignant Hematopoietic Stem and Progenitor Cells in Chronic Myelomonocytic Leukemia Through Reactivation of Retroelements and Innate Immune pathways

Small molecule-induced epigenomic reprogramming of APL blasts leading to antiviral-like response and c-MYC downregulation

Endogenous retrovirus promotes the aberrant T cell differentiation in systemic lupus erythematosus via RIG-I pathway

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