Transcriptional repression in macrophages—basic mechanisms and alterations in metabolic inflammatory diseases

Abstract

Macrophage differentiation and signal responses are coordinated by closely linked transcriptional and epigenomic mechanisms that trigger gene expression. In contrast to well-characterized transcriptional activation pathways in response to diverse metabolic and inflammatory signals, we just begin appreciating that transcriptional repression is equally important. Here, we will highlight macrophage pathways that are controlled by multifaceted repression events, along with a discussion of underlying regulatory mechanisms and components. We will particularly discuss pro-versus anti-inflammatory action of a fundamental corepressor complex, transcription factor cross-talk, repression at enhancers and during elongation, and diverse corepressor knockout mouse models. We will finally emphasize how alterations of macrophage repression pathways in humans contribute to, or even cause, metabolic inflammatory diseases such as obesity and type 2 diabetes.

G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide‐induced ATP‐binding cassette transporter A1 expression in macrophages

“…Cholesterol efflux represents a major mechanism of macrophage cholesterol removal and recycling. ABCA1 and ABCG1 are major macrophage cholesterol transporters involved in cholesterol efflux, both are tightly regulated through TFs and coregulators (1,4,18,25). In this study, we discover a novel mechanism of endotoxin-induced Abca1 expression and cholesterol efflux by the coregulator GPS2 which seems conserved in both mouse and human macrophages.…”

“…Dissecting these complicated intrinsic connections between gene-specific chromatin structure, TF and coregulator composition remains a challenging task and goes beyond the resolution of today's applied experimental approaches. [For further discussion, see our review (25). ]…”

“…Our previous work had demonstrated that GPS2 cooperates with other subunits of the HDAC3 corepressor complex to repress transcription of inflammatory genes (25), but whether the complex is involved in GPS2-dependent activation of Abca1 remained to be clarified. We therefore used published ChIP-seq data to analyze the corepressor complex cistrome (i.e., genome-wide chromatin-binding patterns of individual subunits) at the Abca1 gene locus in BMDMs (26).…”

“…G protein pathway suppressor 2 (GPS2) is an epigenome modulator involved in inflammatory gene regulation that acts in many contexts as a core subunit of a fundamental chromatin-modifying corepressor complex containing histone deacetylase 3 (HDAC3), NCOR, and silencing mediator of retinoid and thyroid receptors (SMRT, also NCOR2) (25). GPS2 interplays with TFs, such as c-Jun (26), and several lipid-sensing nuclear receptors (27)(28)(29)(30)(31).…”

Immunity meets metabolism and then they start talking

“…Their immunophenotype and effector functions are determined by the tissue milieu they reside in, and influenced by metabolic processes. On the one hand, we have reviews dissecting the basic molecular or metabolic processes at work in macrophages such as transcriptional repression , nuclear receptor action , and the effect of the Krebs cycle . On the other, we present reviews looking at the interaction of metabolism and macrophage biology in physiological and pathological processes such as normal skeletal muscle regeneration , tumor progression , and atherosclerosis .…”