Global Modulation in DNA Epigenetics during Pro-Inflammatory Macrophage Activation

Jain, Nikhil; Shahal, Tamar; Gabrieli, Tslil; Gilat, Noa; Torchinsky, Dmitry; Michaeli, Yael; Vogel, Viola; Ebenstein, Yuval

doi:10.1101/587311

Cited by 10 publications

(11 citation statements)

References 53 publications

(37 reference statements)

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“…The epigenetic level of regulation is critical for the differentiation and functional programming of macrophages [ 15 , 113 ]. There are three levels of epigenetic control of macrophages differentiation and activation: DNA methylation, histone modifications, and microRNA [ 15 , 114 ].…”

Section: Epigenetic Regulation Of Tamsmentioning

confidence: 99%

“…TET2 expression is increased in intratumoral myeloid cells, both in a mouse model of melanoma and in melanoma patients, that is dependent on an IL-1R-MyD88 pathway [ 135 ]. Recently, the combination of mass spectrometry and single molecular imaging demonstrated that LPS induces global changes in DNA methylation of the genome of murine macrophages [ 113 , 134 ].…”

Section: Epigenetic Regulation Of Tamsmentioning

confidence: 99%

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Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Larionova

Kazakova

Patysheva

et al. 2020

Cancers

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Macrophages are key innate immune cells in the tumor microenvironment (TME) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. The present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. We summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro- and anti-tumor activities. We also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex TME. We have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.

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Section: Epigenetic Regulation Of Tamsmentioning

confidence: 99%

Section: Epigenetic Regulation Of Tamsmentioning

confidence: 99%

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Larionova

Kazakova

Patysheva

et al. 2020

Cancers

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“…Furthermore, these results by sequence analysis motivated us to determine the biological function of porcine DNMT3B. Given the reported data that expression of DNMT3B is downregulated in LPS-activated mouse macrophages, which is associated with the global demethylation of DNA [ 28 ], thus we chose the LPS-activated PAM as our model for the functional analysis of porcine DNMT3B. Since the alteration of DNMT3B in the LPS-stimulated porcine alveolar macrophages remains unknown, we first investigated the expression profile of DNMT3B in the LPS-activated PAM.…”

Section: Resultsmentioning

confidence: 99%

Identification of DNMT3B2 as the Predominant Isoform of DNMT3B in Porcine Alveolar Macrophages and Its Involvement in LPS-Stimulated TNF-α Expression

Zhang

Xiang

et al. 2020

Genes

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DNA methyltransferase 3B (DNMT3B) as one member of the DNMT family functions as a de novo methyltransferase, characterized as more than 30 splice variants in humans and mice. However, the expression patterns of DNMT3B in pig as well as the biological function of porcine DNMT3B remain to be determined. In this study, we first examined the expression patterns of DNMT3B in porcine alveolar macrophages (PAM). We demonstrated that only DNMT3B2 and DNMT3B3 were the detectable isoforms in PAM. Furthermore, we revealed that DNTM3B2 was the predominant isoform in PAM. Next, in the model of LPS (lipopolysaccharide)-activated PAM, we showed that in comparison to the unstimulated PAM, (1) expression of DNTM3B is reduced; (2) the methylation level of TNF-α gene promoter is decreased. We further establish that DNMT3B2-mediated methylation of TNF-α gene promoter restricts induction of TNF-α in the LPS-stimulated PAM. In summary, these findings reveal that DNMT3B2 is the predominant isoform in PAM and its downregulation contributes to expression of TNF-α via hypomethylation of TNF-α gene promoter in the LPS-stimulated PAM.

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“…The microscopy images were analyzed using a custom-made software [ [47] , [48] , [49] ]. The total DNA length of each molecule was estimated and the number of colocalized Aminoallyl-dUTP-ATTO-647 N spots on each molecule was counted.…”

Section: Methodsmentioning

confidence: 99%

Quantifying DNA damage induced by ionizing radiation and hyperthermia using single DNA molecule imaging

Singh

Johansson

Torchinsky

et al. 2020

Translational Oncology

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Ionizing radiation (IR) is a common mode of cancer therapy, where DNA damage is the major reason of cell death. Here, we use an assay based on fluorescence imaging of single damaged DNA molecules isolated from radiated lymphocytes, to quantify IR induced DNA damage. The assay uses a cocktail of DNA-repair enzymes that recognizes and excises DNA lesions and then a polymerase and a ligase incorporate fluorescent nucleotides at the damage sites, resulting in a fluorescent “spot” at each site. The individual fluorescent spots can then be counted along single stretched DNA molecules and the global level of DNA damage can be quantified. Our results demonstrate that inclusion of the human apurinic/apyrimidinic endonuclease 1 (APE1) in the enzyme cocktail increases the sensitivity of the assay for detection of IR induced damage significantly. This optimized assay also allowed detection of a cooperative increase in DNA damage when IR was combined with mild hyperthermia, which is sometimes used as an adjuvant in IR therapy. Finally, we discuss how the method may be used to identify patients that are sensitive to IR and other types of DNA damaging agents.

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Global Modulation in DNA Epigenetics during Pro-Inflammatory Macrophage Activation

Cited by 10 publications

References 53 publications

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Identification of DNMT3B2 as the Predominant Isoform of DNMT3B in Porcine Alveolar Macrophages and Its Involvement in LPS-Stimulated TNF-α Expression

Quantifying DNA damage induced by ionizing radiation and hyperthermia using single DNA molecule imaging

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