High-mobility group N proteins are required for regulation of antigen-presentation genes in macrophages

The expression, localization, and secretion of certain chromatin proteins are tightly regulated in response to inflammatory challenges or tissue damage. High mobility group (HMG) nucleosome-binding proteins can translocate out of the nucleus to act as alarmins in immune cell communications. The consequences of nuclear depletion of HMGs in genome organization and gene regulation are not understood in the context of innate immunity. Here, we report alterations of tissue-specific macrophage transcriptome using a genetic knockout (KO) of HMGN1 and HMGN2, an HMGN double knockout mouse line. Lack of both HMGN proteins disrupted the expression of key macrophage genes, including those encoding MHCs, M-CSF, and ApoE, as well as acute responses to LPS, in a sex-dependent manner. These transcriptional effects were associated with concomitant changes in chromatin accessibility, as profiled by an assay for transposase accessible chromatin by sequencing, in regulatory sites distal and proximal to the corresponding genes. These findings highlight the importance of macrophage HMGNs in maintaining tissue-specific gene expression and supporting inflammatory responses.