Monocyte polarization: The relationship of genome-wide changes in H4 acetylation with polarization

Center for Bioinformatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Genes and immunity (Impact Factor: 2.91). 03/2011; 12(6):445-56. DOI: 10.1038/gene.2011.17
Source: PubMed


The character of monocytes is both molded by and contributes to ongoing immune responses. We hypothesized that monocyte polarization could have durable qualities and these would be mediated partly by changes in the chromatin. We defined genome-wide expression and histone H4 acetylation (H4ac) changes after γ-interferon (IFN), α-IFN and interleukin-4 treatment. To identify genes with altered potential for expression, we stimulated polarized monocytes and identified genes up- or downregulated after polarization and stimulation but not either treatment alone. We also defined durability after an 18-h or 3-day washout. Genes uniquely regulated after the combination of polarization and stimulus were durably altered, with 51% of the effects being durable. This gene set was highly enriched for cytokine-induced alterations in H4ac, with P-values ranging from 10(-24) to 10(-37). Certain regulons defined by patterns of expression were also associated with altered H4ac, with P-values ranging from 10(-4) to 10(-29). Networking software revealed a high density of mitogen-activated protein (MAP) kinase nodes in these clusters. Therefore, some changes in monocyte gene expression were sustained over a 3-day period. These durably altered gene sets were enriched for changes in H4ac and were associated with potential MAP kinase effects.

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    • "IRF1, IRF2, and RFX1 were previously identified by us as potential regulators of genes with altered histone H4 acetylation [23], [24], [25]. These transcription factors, now identified as potential regulators of the SLE transcriptome, could integrate inflammatory and interferon signals. "
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    ABSTRACT: Gene expression studies of peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE) have demonstrated a type I interferon signature and increased expression of inflammatory cytokine genes. Studies of patients with Aicardi Goutières syndrome, commonly cited as a single gene model for SLE, have suggested that accumulation of non-coding RNAs may drive some of the pathologic gene expression, however, no RNA sequencing studies of SLE patients have been performed. This study was designed to define altered expression of coding and non-coding RNAs and to detect globally altered RNA processing in SLE. Purified monocytes from eight healthy age/gender matched controls and nine SLE patients (with low-moderate disease activity and lack of biologic drug use or immune suppressive treatment) were studied using RNA-seq. Quantitative RT-PCR was used to validate findings. Serum levels of endotoxin were measured by ELISA. We found that SLE patients had diminished expression of most endogenous retroviruses and small nucleolar RNAs, but exhibited increased expression of pri-miRNAs. Splicing patterns and polyadenylation were significantly altered. In addition, SLE monocytes expressed novel transcripts, an effect that was replicated by LPS treatment of control monocytes. We further identified increased circulating endotoxin in SLE patients. Monocytes from SLE patients exhibit globally dysregulated gene expression. The transcriptome is not simply altered by the transcriptional activation of a set of genes, but is qualitatively different in SLE. The identification of novel loci, inducible by LPS, suggests that chronic microbial translocation could contribute to the immunologic dysregulation in SLE, a new potential disease mechanism.
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    • "There are other studies that have shown a global acetylation pattern of histone H3 and H4 in active SLE CD4+ T cells [123]. Also, monocytes, which are important in SLE renal disease, have been shown to have an altered acetylation pattern of histone H4 thus increasing the expression of interferon (IFN) genes that play a key role in SLE pathogenesis [124–126]. "
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    • "Furthermore, monocyte (and potentially macrophage) polarization was heterogenous with respect to durability. This systems approach identified mitogen-activated protein (MAP) kinases as central to the polarization process consistent recent studies highlighting the role of MAP kinases in histone modification [58]. Thus, systems biology will keep providing a constantly updated global view of the networks regulating or involved in macrophage polarization, allowing us to evaluate key issues related to macrophage heterogeneity and plasticity. "
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