Epigenetic Regulation of Monocyte and Macrophage Function

Hoeksema, Marten A.; Winther, Menno P.J. de

doi:10.1089/ars.2016.6695

Cited by 95 publications

(73 citation statements)

References 145 publications

(174 reference statements)

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“…Overall, we found that stimulation drives dramatic changes in regulatory landscapes of B and T cells. In contrast, we saw limited effects in innate lineage cells ( Figure S3A,B), perhaps because the chromatin response in the innate lineage cells is poised or transient (22,24,25). Figure 2A).…”

Section: Stimulation Results In Large-scale Chromatin and Gene Expresmentioning

confidence: 80%

Landscape of stimulation-responsive chromatin across diverse human immune cells

Calderon

Nguyen

Mezger

et al. 2018

Preprint

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The immune system is controlled by a balanced interplay among specialized cell types transitioning between resting and stimulated states. Despite its importance, the regulatory landscape of this system has not yet been fully characterized. To address this gap, we collected ATAC-seq and RNA-seq data under resting and stimulated conditions for 25 immune cell types from peripheral blood of four healthy individuals, and seven cell types from three fetal thymus samples. We found that stimulation caused widespread chromatin remodeling, including a large class of response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulation-responsive elements from distinct cell types, highlighting the critical importance of these cell states in autoimmunity. Use of allele-specific read-mapping identified thousands of variants that alter chromatin accessibility in particular conditions. Notably, variants associated with changes in stimulation-specific chromatin accessibility were not enriched for associations with gene expression regulation in whole blood -a tissue commonly used in eQTL studies. Thus, large-scale maps of variants associated with gene regulation lack a condition important for understanding autoimmunity. As a proof-of-principle we identified variant rs6927172, which links stimulated T cell-specific chromatin dysregulation in the TNFAIP3 locus to ulcerative colitis and rheumatoid arthritis. Overall, our results provide a broad resource of chromatin landscape dynamics and highlight the need for large-scale characterization of effects of genetic variation in stimulated cells.

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Section: Stimulation Results In Large-scale Chromatin and Gene Expresmentioning

confidence: 80%

Landscape of stimulation-responsive chromatin across diverse human immune cells

Calderon

Nguyen

Mezger

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…Among them, monocyte activation and proliferation are critical steps corresponding to bacterial infection [27]. Mounting evidence shows that epigenetics modulates host innate immunity against exogenous pathogens through multi-channel mechanisms involving in DNA methylation, histone post-translational modification and the activity of non-coding RNAs [28, 29].…”

Section: Introductionmentioning

confidence: 99%

LPS promotes HBO1 stability via USP25 to modulate inflammatory gene transcription in THP-1 cells

Chen

Lai

et al. 2018

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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The histone acetyltransferase HBO1 (Histone acetyltransferase binding to origin recognition complex 1, Myst2/Kat7) participates in a range of life processes including DNA replication and tumorigenesis. Recent studies revealed that HBO1 is involved in gene transcriptional activation. However, the molecular behavior of HBO1 in inflammation is yet to be studied. Here we report that endotoxin lipopolysaccharide (LPS) elevates HBO1 protein level via up-regulating UPS25 (ubiquitin specific peptidase 25) and alters inflammatory gene transcription in THP-1 monocytes and in human primary macrophages. LPS protects HBO1 from ubiquitin proteasomal degradation without significantly altering its transcription. By immunoprecipitation, we identified that HBO1 associates with a deubiquitinating enzyme USP25 in THP-1 cells. LPS increases protein level of USP25 resulting in accumulation of HBO1 by suppression of HBO1 ubiquitination. Stabilized-HBO1 modulates inflammatory gene transcription in THP-1 cells. These findings indicate that USP25 promotes stability of HBO1 in bacterial infection thereby enhances HBO1-mediated inflammatory gene transcription.

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“…This suggests that cells retain the "memory" of this context in culture. Indeed, the concept of epigenetic memory of innate immune cells such as macrophages has been proposed to play an important role in modulating immune responses (48)(49)(50)(51). Although this has been mainly studied in the context of pro-inflammatory stimuli and the regulation of pro-inflammatory gene expression, there are also reports showing a distinct metabolic environment (for instance in type 2 diabetes) can epigenetically imprint bone marrow progenitor cells that can derive into a "pre-programmed macrophage state associated with changes in gene expression (51).…”

Section: Discussionmentioning

confidence: 99%

Disrupting myeloid-specific LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation

Bécares-Salles

Louie

et al. 2017

Preprint

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Macrophages are key immune cells for the initiation and development of atherosclerotic lesions.However, the macrophage regulatory nodes that determine how lesions progress in response to dietary challenges are not fully understood. Liver X receptors (LXRs) are sterol-regulated transcription factors which play a central role in atherosclerosis by integrating cholesterol homeostasis and immunity. LXR pharmacological activation elicits a robust anti-atherosclerotic transcriptional program in macrophages that can be affected by LXRα S196 phosphorylation in vitro. To investigate the impact of these transcriptional changes in atherosclerosis development, we have generated mice carrying a Ser-to-Ala mutation in myeloid cells in the LDLR-deficient atherosclerotic background (M-S196A Ldlr-KO ). M-S196A Ldlr-KO mice fed a high fat diet exhibit increased atherosclerotic plaque burden and lesions with smaller necrotic cores and thinner fibrous caps. These diet-induced phenotypic changes are consistent with a reprogramed macrophage transcriptome promoted by LXRα-S196A during atherosclerosis development.Remarkably, expression of several proliferation-promoting factors including the proto-oncogene FoxM1 and its targets are induced by LXRα-S196A. This is consistent with increased proliferation of plaque-resident cells in M-S196A Ldlr-KO mice. Moreover, disrupted LXRα phosphorylation increases expression of phagocytic molecules resulting in increased apoptotic cell removal by macrophages, explaining the reduced necrotic cores. Finally, the macrophage transcriptome promoted by LXRα-S196A under dietary perturbation is markedly distinct from that revealed by LXR ligand activation, highlighting the singularity of this post-translational modification. Overall, our findings demonstrate that LXRα phosphorylation at S196 is an important determinant of atherosclerotic plaque development through selective changes in gene transcription that affect multiple pathways.

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Epigenetic Regulation of Monocyte and Macrophage Function

Abstract: The key challenges in the upcoming years will be to study epigenetic changes in human disease and to better understand how epigenetic pathways control the inflammatory repertoire in disease. Antioxid. Redox Signal. 25, 758-774.

Cited by 95 publications

References 145 publications

Landscape of stimulation-responsive chromatin across diverse human immune cells

Landscape of stimulation-responsive chromatin across diverse human immune cells

LPS promotes HBO1 stability via USP25 to modulate inflammatory gene transcription in THP-1 cells

Disrupting myeloid-specific LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation

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