ARTD1 Suppresses Interleukin 6 Expression by Repressing MLL1-Dependent Histone H3 Trimethylation

Abstract

b ADP-ribosyltransferase diphtheria-toxin like 1/poly(ADP-ribose) polymerase 1 (ARTD1/PARP1) is a chromatin-associated protein in the nucleus and plays an important role in different cellular processes such as regulation of gene transcription. ARTD1 has been shown to coregulate the inflammatory response by modulating the activity of the transcription factor nuclear factor B (NF-B), the principal regulator of interleukin 6 (IL-6), an important inflammatory cytokine implicated in a variety of diseases such as cancer. However, to what extent and how ARTD1 regulates IL-6 transcription has not been clear. Here, we show that ARTD1 suppresses lipopolysaccharide (LPS)-induced IL-6 expression in macrophages, without affecting the recruitment of the NF-B subunit RelA to the IL-6 promoter and independent of its enzymatic activity. Interestingly, knockdown of ARTD1 did not alter H3 occupancy but increased LPS-induced trimethylation of histone 3 at lysine 4 (H3K4me3), a hallmark of transcriptionally active genes. We found that ARTD1 mediates its effect through the methyltransferase MLL1, by catalyzing H3K4me3 at the IL-6 promoter and forming a complex with NF-B. These results demonstrate that ARTD1 modulates IL-6 expression by regulating the function of an NF-B enhanceosome complex, which involves MLL1 and does not require ADP-ribosylation.

Global Transcriptome Analysis Reveals That Poly(ADP-Ribose) Polymerase 1 Regulates Gene Expression through EZH2

“…Furthermore, the link between PARP activity and B cell function is supported by the observation that transcription factors known to contribute to the immune response, such as IL-2 and IFN-␥, most likely play a role in PARP-mediated gene regulation. PARP1 was recently demonstrated to modulate the expression of IL-6 in macrophages, supporting our observation of a role of PARP1 in the immune response (52). Although IL-6 regulation is independent of PARP1 activity in LCL cells, our data show that IL-2 and IFN-␥ may be dependent on PARP1 activity, reflecting different mechanisms of PARP1-mediated gene expression during the immune response.…”

The STAT4/MLL1 Epigenetic Axis Regulates the Antimicrobial Functions of Murine Macrophages

“…Previous studies suggest that MLL1 expression and function can be regulated by NF-κB dependent signals(14, 25). As NF-κB signal transduction plays a central role in classical activation, we sought to determine if MLL1 expression and/or global H3K4me1/2/3 modifications were increased in macrophages in response to classical activation stimuli.…”

“…Previous reports have identified an important role for NF-κB signal transduction in response to TNFα for the regulation of MLL1 expression and function in macrophages(14, 25). Our studies identified potent upregulation of Mll1 mRNA in response to LPS stimulation, which primarily signals through TLR4 and NF-κB.…”

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

“…Evidence suggests that ADP-ribosylation participates in inflammation (Bai and Virág 2012;Rosado et al 2013;Kunze and Hottiger 2019). PARP1 has been implicated in the mechanisms for responses (e.g., proinflammatory cytokine expression) of macrophages or macrophage-like cell lines to pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS) (Hassa et al 2005;Liu et al 2012a;Yang et al 2014;Minotti et al 2015;Bohio et al 2019). Some responses involve the interplay between PARP1 and nuclear factor κB (NF-κB), a key B A Figure 1.…”

“…(P) Phosphate group; (ADPr) ADP-ribose; (Ac) acetyl modification; (yellow ciricle) ubiquitin. transcription factor in immunity and various other biological processes (Hassa and Hottiger 1999;Hassa et al 2005;Liu et al 2012a;Minotti et al 2015;Bohio et al 2019;Kunze and Hottiger 2019). Using PARP1-deficient mice Oliver et al (1999) provided evidence that PARP1 promotes NF-κB activation in macrophages in vivo.…”