Histone Methylation Mechanisms Modulate the Inflammatory Response of Periodontal Ligament Progenitors

Francis, Marybeth; Pandya, Mirali; Gopinathan, Gokul; Lyu, Huling; Ma, Wei; Foyle, Deborah; Nares, Salvadore; Luan, Xianghong

doi:10.1089/scd.2019.0125

Cited by 27 publications

(27 citation statements)

References 49 publications

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“…2A, B), while H3K27 was reduced on IL-6 and defensin b-4 inflammatory gene promoters, suggesting a more open chromatin and more active transcriptional state on those promoters. These findings match earlier studies from our laboratory also reporting a global reduction in H3K27me3 enrichment on inflammation response gene promoters (Francis et al 2019). As mentioned, H3K27me3 is a bivalent chromatin mark—a mark that is most easily affected by dynamic changes in levels of inflammation.…”

Section: Histone Methylation Alteration In Periodontal Disease: Animasupporting

confidence: 92%

Histone Methylation: Achilles Heel and Powerful Mediator of Periodontal Homeostasis

et al. 2020

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The packaging of DNA around nucleosomes exerts dynamic control over eukaryotic gene expression either by granting access to the transcriptional machinery in an open chromatin state or by silencing transcription via chromatin compaction. Histone methylation modification affects chromatin through the addition of methyl groups to lysine or arginine residues of histones H3 and H4 by means of histone methyl transferases or histone demethylases. Changes in histone methylation state modulate periodontal gene expression and have profound effects on periodontal development, health, and therapy. At the onset of periodontal development, progenitor cell populations such as dental follicle cells are characterized by an open H3K4me3 chromatin mark on RUNX2, MSX2, and DLX5 gene promoters. During further development, periodontal progenitor differentiation undergoes a global switch from the H3K4me3 active methyl mark to the H3K27me3 repressive mark. When compared with dental pulp cells, periodontal neural crest lineage differentiation is characterized by repressive H3K9me3 and H3K27me3 marks on typical dentinogenesis-related genes. Inflammatory conditions as they occur during periodontal disease result in unique histone methylation signatures in affected cell populations, including repressive H3K9me3 and H3K27me3 histone marks on extracellular matrix gene promoters and active H3K4me3 marks on interleukin, defensin, and chemokine gene promoters, facilitating a rapid inflammatory response to microbial pathogens. The inflammation-induced repression of chromatin on extracellular matrix gene promoters presents a therapeutic opportunity for the application of histone methylation inhibitors capable of inhibiting suppressive trimethylation marks. Furthermore, inhibition of chromatin coregulators through interference with key inflammatory mediators such as NF-kB by means of methyltransferase inhibitors provides another avenue to halt the exacerbation of the inflammatory response in periodontal tissues. In conclusion, histone methylation dynamics play an intricate role in the fine-tuning of chromatin states during periodontal development and harbor yet-to-be-realized potential for the treatment of periodontal disease.

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Section: Histone Methylation Alteration In Periodontal Disease: Animasupporting

confidence: 92%

Histone Methylation: Achilles Heel and Powerful Mediator of Periodontal Homeostasis

et al. 2020

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“… 39 Inflammation may lead to hypomethylation and subsequent up-regulation of DEFA4 . 40 These findings lead us to propose that hypomethylation-induced up-regulation of hub genes contributes to the development of sepsis-induced ARDS. Regrettably, IRF7 was upregulated and highly affecting the toll like receptor signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Identification of Genes with Altered Methylation and Its Role in Early Diagnosis of Sepsis-Induced Acute Respiratory Distress Syndrome

Feng¹,

Pang²,

He³

et al. 2021

IJGM

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Purpose Early diagnosis of sepsis-induced acute respiratory distress syndrome (ARDS) is critical for effective treatment. We aimed to identify early stage biomarkers. Materials and Methods Differentially expressed genes were identified in whole blood samples from patients with sepsis or ARDS based on the Gene Expression Omnibus (GEO) datasets GSE32707, GSE54514 and GSE10361. Functional enrichment analysis explored the biological characteristics of differentially expressed genes. Genes with high functional connectivity based on a protein-protein interaction network were marked as hub genes, which were validated using the GEO dataset GSE76293, and a gene set variation analysis index (GSVA) was assigned. Diagnostic and predictive ability of the hub genes were assessed by receiver operating characteristic (ROC) curve analysis. DNA methylation levels of hub genes were quantified using the GEO dataset GSE67530. Results Forty-one differentially expressed genes were shared between sepsis-specific and ARDS-specific datasets. MAP2K2 and IRF7 functional activity was highly connected in sepsis-induced ARDS. Hub genes included RETN, MVP, DEFA4, CTSG, AZU1, FMNL1, RBBP7, POLD4, RIN3, IRF7. ROC curve analysis of the hub gene GSVA index showed good diagnostic ability in sepsis or ARDS. Among genes related to sepsis-induced ARDS, 17 were differentially methylated. Principal component analysis and heatmaps indicated that gene methylation patterns differed significantly between ARDS patients and controls. Conclusion We identified a genetic profile specific to early-stage sepsis-induced ARDS. The abnormal expression of these genes may be caused by hypomethylation, which may serve as a biomarker for early diagnosis of ARDS.

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“…The reaction was stopped with 125 mM glycine. Nuclei were prepared from 1 × 10 6 cells and ChIP was performed as described previously (Francis et al 2019). The antibodies used for ChIP analysis were against histone H3K4me3, H3K9me3, H3K27me3, SETD1B, and p65 (ab8580, ab70378, ab8898, ab6147, Abcam; sc-71x, Santa Cruz).…”

Section: Methodsmentioning

confidence: 99%

“…Total RNAs were isolated from mouse periodontal tissues or human PDL cells using the RNeasy Plus Mini Kit according to the manufacturer’s instructions (Qiagen). Then, 2 µg total RNA was applied toward complementary DNA (cDNA) generation, and quantitative reverse transcription PCR (RT-qPCR) was performed using sequence specific primers (Appendix Table 1) and SYBR green Master Mix as described previously (Francis et al 2019). β-Actin was used as an internal control.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we have demonstrated that inflammation triggers repressive histone mark enrichment on extracellular matrix gene promoters and active marks on defensins and chemokines (Francis et al 2019). In the present study, we have focused on SETD1B as a histone methyltransferase that specifically methylates the lysine 4 position of histone H3.…”

Section: Introductionmentioning

confidence: 99%

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SETD1 and NF-κB Regulate Periodontal Inflammation through H3K4 Trimethylation

Francis¹,

Gopinathan

Salapatas³

et al. 2020

J Dent Res

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The inflammatory response to periodontal pathogens is dynamically controlled by the chromatin state on inflammatory gene promoters. In the present study, we have focused on the effect of the methyltransferase SETD1B on histone H3 lysine K4 (H3K4) histone trimethylation on inflammatory gene promoters. Experiments were based on 3 model systems: 1) an in vitro periodontal ligament (PDL) cell culture model for the study of SETD1 function as it relates to histone methylation and inflammatory gene expression using Porphyromonas gingivalis lipopolysaccharide (LPS) as a pathogen, 2) a subcutaneous implantation model to determine the relationship between SETD1 and nuclear factor κB (NF-κB) through its activation inhibitor BOT-64, and 3) a mouse periodontitis model to test whether the NF-κB activation inhibitor BOT-64 reverses the inflammatory tissue destruction associated with periodontal disease. In our PDL progenitor cell culture model, P. gingivalis LPS increased H3K4me3 histone methylation on IL-1β, IL-6, and MMP2 gene promoters, while SETD1B inhibition decreased H3K4me3 enrichment and inflammatory gene expression in LPS-treated PDL cells. LPS also increased SETD1 nuclear localization in a p65-dependent fashion and the nuclear translocation of p65 as mediated through SETD1, suggestive of a synergistic effect between SETD1 and p65 in the modulation of inflammation. Confirming the role of SETD1 in p65-mediated periodontal inflammation, BOT-64 reduced the number of SETD1-positive cells in inflamed periodontal tissues, restored periodontal tissue integrity, and enhanced osteogenesis in a periodontal inflammation model in vivo. Together, these results have established the histone lysine methyltransferase SETD1 as a key factor in the opening of the chromatin on inflammatory gene promoters through histone H3K4 trimethylation. Our studies also confirmed the role of BOT-64 as a potent molecular therapeutic for the restoration of periodontal health through the inhibition of NF-κB activity and the amelioration of SETD1-induced chromatin relaxation.

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Histone Methylation Mechanisms Modulate the Inflammatory Response of Periodontal Ligament Progenitors

Cited by 27 publications

References 49 publications

Histone Methylation: Achilles Heel and Powerful Mediator of Periodontal Homeostasis

Histone Methylation: Achilles Heel and Powerful Mediator of Periodontal Homeostasis

Identification of Genes with Altered Methylation and Its Role in Early Diagnosis of Sepsis-Induced Acute Respiratory Distress Syndrome

SETD1 and NF-κB Regulate Periodontal Inflammation through H3K4 Trimethylation

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