Interferons reshape the 3D conformation and accessibility of macrophage chromatin

Platanitis, Ekaterini; Gruener, Stephan; Geetha, Aarathy Ravi Sundar Jose; Boccuni, Laura; Vogt, Alexander; Novatchkova, Maria; Sommer, Andreas; Barozzi, Iros; Müller, Mathias; Decker, Thomas

doi:10.1016/j.isci.2022.103840

Cited by 27 publications

(38 citation statements)

References 70 publications

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“…Macrophage stimulation with IFN-β has also been shown to remodel 3D chromatin structure and increases CA at many interferon-stimulated genes. Notably, this effect was prominent at Oas, Mx1,2 and Ifit1 genes (Platanitis et al 2022), which are among the subset of genes we show to be DAR and DEG upon Mtb infection. In fibroblasts, stimulation with IFN-β also leads to accumulation of H3K36me3 at Oas1, Mx1 and Ifit1, termed "memory interferon-stimulated genes", mediating enhanced upregulation upon re-stimulation (Kamada et al 2018).…”

Section: Discussionmentioning

confidence: 60%

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Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

Madden

Hamra

Berton

et al. 2022

Preprint

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Tuberculosis, a deadly infectious lung disease caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of bacterial disease-related deaths worldwide. The success of Mtb as a human pathogen depends on its ability to manipulate host immune response pathways, many of which are regulated by epigenetic mechanisms that control the accessibility of chromatin to the transcriptional machinery. Recent reports suggest that host phosphatases, such as PPM1A, may play a role in the regulation of chromatin accessibility during bacterial infections. However, changes in genome-wide chromatin accessibility during Mtb infection and whether PPM1A plays a role in this process remains unknown. Using combinatorial chromatin accessibility (ATAC-seq) and transcriptomics (RNA-seq) profiling of wild-type (WT), PPM1A knockout (ΔPPM1A) and PPM1A overexpressing (PPM1A+) macrophages, we demonstrate that Mtb infection induces global chromatin remodeling consistent with changes in gene expression signatures. The strongest concordant chromatin accessibility and gene expression signature triggered by Mtb infection was enriched for genes involved in the type I interferon (IFN) signaling pathways. Modulation of PPM1A expression results in altered chromatin accessibility signatures during Mtb infection that are reflected in the total number, chromosome location and directionality of change. Transcription factor motif analysis revealed an enrichment for transcription factors involved in the type I IFN pathway during Mtb infection, including IRF4, MEF2A, CEBPD and JDP2. In contrast, both deletion and overexpression of PPM1A produced unique transcription factor enrichment signatures linked to the genomic regions with altered chromatin accessibility. Our study demonstrates that altered type I IFN responses in Mtb-infected macrophages occurs as a result of genome-wide changes in chromatin accessibility, and that PPM1A likely plays a role in a subset of these signatures.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

Madden

Hamra

Berton

et al. 2022

Preprint

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“…3) Their response may be directly affected by cohesin depletion, which may prevent the formation of LPS-induced loops that are necessary for a normal response. Interaction landscapes can rapidly change during macrophage stimulation, as exemplified by conformation changes observed after 2 h of IFNγ stimulation in mouse macrophages 57 or 2 h of LPS treatment of THP1 cells 58 . NFκB and AP-1, the main TF driving the early responses to pathogen-associated molecular patterns like LPS, frequently bind promoter-distal sites 59 and may require cohesin to properly interact with their target promoters during activation.…”

Section: Discussionmentioning

confidence: 99%

Postmitotic differentiation of human monocytes requires cohesin-structured chromatin

et al. 2022

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Cohesin is a major structural component of mammalian genomes and is required to maintain loop structures. While acute depletion in short-term culture models suggests a limited importance of cohesin for steady-state transcriptional circuits, long-term studies are hampered by essential functions of cohesin during replication. Here, we study genome architecture in a postmitotic differentiation setting, the differentiation of human blood monocytes (MO). We profile and compare epigenetic, transcriptome and 3D conformation landscapes during MO differentiation (either into dendritic cells or macrophages) across the genome and detect numerous architectural changes, ranging from higher level compartments down to chromatin loops. Changes in loop structures correlate with cohesin-binding, as well as epigenetic and transcriptional changes during differentiation. Functional studies show that the siRNA-mediated depletion of cohesin (and to a lesser extent also CTCF) markedly disturbs loop structures and dysregulates genes and enhancers that are primarily regulated during normal MO differentiation. In addition, gene activation programs in cohesin-depleted MO-derived macrophages are disturbed. Our findings implicate an essential function of cohesin in controlling long-term, differentiation- and activation-associated gene expression programs.

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“…The latter process might be related to the loss of long-range interactions observed during induction of differentiation in mouse ESCs (Feldmann et al, 2020). Furthermore, a recent study describes the reorganization of the 3D genome around ISG loci upon both IFNβ and IFNγ treatment, which involves loop formation, nucleosome remodeling and an increase of DNA accessibility (Platanitis et al, 2021). Thus, it is emerging that a reorganization of long-range chromatin interactions represents an important part of IFN mediated gene induction.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic signals that direct cell type specific interferon beta response in mouse cells

Muckenhuber

Seufert

Müller-Ott

et al. 2022

Preprint

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The antiviral response induced by type I interferon (IFN) via the JAK-STAT signaling cascade activates hundreds of IFN-stimulated genes (ISGs). While this response occurs essentially in all human and mouse tissues it varies between different cell types. However, the linkage between the underlying epigenetic features and the ISG pattern of a given cell is not well understood. We mapped ISGs, binding sites of the STAT1 and STAT2 transcription factors and chromatin features in three different mouse cell types (embryonic stem cells, neural progenitor cells and embryonic fibroblasts) before and after treatment with IFNβ. The analysis included gene expression, chromatin accessibility and histone H3 lysine modification by acetylation (ac) and mono-/tri-methylation (me1, me3). A large fraction of ISGs and STAT binding sites were cell type specific with promoter binding of a STAT1-STAT2 complex (STAT1/2) being a key driver of ISG induction. Furthermore, STAT1/2 binding to putative enhancers at intergenic and intronic sites induced ISG expression as inferred from a chromatin co-accessibility analysis. STAT1/2 binding was dependent on the chromatin context and positively correlated with pre-existing H3K4me1 and H3K27ac marks in an open chromatin state while the presence of H3K27me3 had an inhibitory effect. Thus, chromatin features present before stimulation represent an additional regulatory layer for the cell type specific antiviral response.

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Interferons reshape the 3D conformation and accessibility of macrophage chromatin

Cited by 27 publications

References 70 publications

Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

Postmitotic differentiation of human monocytes requires cohesin-structured chromatin

Epigenetic signals that direct cell type specific interferon beta response in mouse cells

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