ARTD1 suppresses interleukin 6 expression by repressing MLL1-dependent histone H3 trimethylation

Abstract

ADP-ribosyltransferase diphtheria-toxin like 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 co-regulate the inflammatory response by modulating the activity of the transcription factor nuclear factor kappa B (NF-κB), the principal regulator of interleukin 6 (IL6), an important inflammatory cytokine implicated in a variety of diseases such as cancer. However, to which extent and how ARTD1 regulates IL6 transcription has not been clear.Here, we show that ARTD1 suppresses LPS-inducedIL6expression in macrophages, without affecting the recruitment of the NF-κB subunit RelA to theIL6promoter 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 theIL6promoter and forming a complex with NF-κB. These results demonstrate that ARTD1 modulatesIL6expression by regulating the function of an NF-κB enhanceosome complex, which involves MLL1 and does not require ADP-ribosylation.