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

Abstract

Macrophages are critical immune cells for the clearance of microbial pathogens and cellular debris from peripheral tissues. Macrophage inflammatory responses are governed by gene expression patterns, and these patterns are often subject to epigenetic control. Chromatin modifications such as histone methylation regulate gene accessibility in macrophages, and macrophage polarization is governed in part by the expression and function of chromatin modifying enzymes. The histone methyltransferase Mixed-Lineage Leukemia 1 (MLL1) preferentially modifies lysine residue 4 on the unstructured protein tail of histone H3. MLL1 expression and function has been shown to be governed by signal transduction pathways that are activated by inflammatory stimuli, such as NF-κB. We therefore sought to investigate the role of MLL1 in mediating macrophage inflammatory responses. Bone marrow-derived macrophages from mice with a targeted MLL1 gene knockout (Lys2-Cre+/− MLL1fx/fx) exhibited decreased proinflammatory gene expression with concurrent decreases in activating histone methylation. However, MLL1-deficient macrophages also exhibited increased phagocytic and bacterial killing activity in vitro. RNA profiling of MLL1 knockout macrophages indicated numerous genes involved with inflammatory responses whose expression was altered in response to Toll-like receptor ligands or proinflammatory cytokines, including signal transducer and activator of transcription 4 (STAT4). STAT4-dependent cytokines such as Type I Interferons were able to drive MLL1 expression in macrophages, and MLL1 knockout macrophages exhibited decreased activating histone methylation in the STAT4 promoter. These results implicate an important role for MLL1-dependent epigenetic regulation of macrophage antimicrobial functions.

The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes

“…We found significant increases in MLL1 in wound macrophages at days 3 and 5, suggesting that MLL1 plays an important role in regulating early macrophage-mediated wound inflammation. To determine whether this early increase in MLL1 in wound macrophages is necessary for healing, we used Mll1 +/− heterozygote mice ( Mll1 −/− are embryonically lethal) to determine whether wounds with decreased MLL1 had impaired early healing (21). We first confirmed that wounds isolated from the Mll1 +/− mice expressed less Mll1 transcript than littermate controls (Fig.…”

“…In mammals, H3K4me3 is controlled by the SET1-MLL family of enzymes (20). Although the role of MLL1 in oncogenesis has been investigated, few studies have examined the role of MLL1 in innate immunity (17,19,21). Furthermore, the function of MLL1 in normal physiology, particularly in wound healing, is unknown.…”

Epigenetic stabilization of DC and DC precursor classical activation by TNFα contributes to protective T cell polarization

“…The acquiescence of phenotypic stability by myeloid cells via epigenetic histone modification has been reported and is an area of intense investigation (2,18,41). The most recognized example is the phenomenon of "trained immunity," when myeloid cells (monocytes and macrophages) acquire properties compatible with immunological memory.…”

Histone Methylation Directs Myeloid TLR4 Expression and Regulates Wound Healing following Cutaneous Tissue Injury

“…In mammals, H3K4me3 is controlled by the SET1/MLL family of enzymes (13). Although the role of MLL1 in oncogenesis has been investigated, few studies have examined the role of MLL1 in innate immunity (10,14,15). We have recently identified that MLL1 may regulate macrophage cytokine expression; however, the role of MLL1 in regulating upstream signaling pathways remains poorly defined (16).…”