Castrillo, A. | bioRxiv Science

bioRxiv2026

An enhancer-centric approach applied to human immune system epigenomes revealed the association of macrophage enhancers with cardiovascular disease

Complex diseases are influenced by both genetic and environmental factors. Immune cells are key mediating interactions with the environment, but the impact of genetic variation on the immune system and how it influences complex diseases is not fully understood. Moreover, most genome-wide analyses (GWAS) variants associated with complex diseases are non-coding and difficult to interpret. Here, we investigated the association of non-coding variants with immune cell enhancers. As part of BLUEPRINT and the International Human Epigenome (IHEC) consortia, we generated and analysed a comprehensive set of epigenomes for human primary immune cells, including 107 epigenomes derived from 749 ChIP-Seq experiments across 24 cell types. We identified multicell enhancer activity patterns across the genome and examined their links with non-coding variants from 518 GWAS traits. This analysis revealed 117 significant associations, including novel links between cardiovascular disease variants and macrophage-specific enhancers that regulate genes involved in lipid metabolism and immunity, such as the gene encoding for the nuclear receptor LXR-alpha (NR1H3) and many of its known target genes. Together, these data will help to better understand the influence of genetic variability in immune function and related diseases.

genomics↗

bioRxiv2017

Disrupting myeloid-specific LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation

Macrophages are key immune cells for the initiation and development of atherosclerotic lesions. However, the macrophage regulatory nodes that determine how lesions progress in response to dietary challenges are not fully understood. Liver X receptors (LXRs) are sterol-regulated transcription factors which play a central role in atherosclerosis by integrating cholesterol homeostasis and immunity. LXR pharmacological activation elicits a robust anti-atherosclerotic transcriptional program in macrophages that can be affected by LXR S196 phosphorylation in vitro. To investigate the impact of these transcriptional changes in atherosclerosis development, we have generated mice carrying a Ser-to-Ala mutation in myeloid cells in the LDLR-deficient atherosclerotic background (M-S196ALdlr-KO). M-S196ALdlr-KO mice fed a high fat diet exhibit increased atherosclerotic plaque burden and lesions with smaller necrotic cores and thinner fibrous caps. These diet-induced phenotypic changes are consistent with a reprogramed macrophage transcriptome promoted by LXR-S196A during atherosclerosis development. Remarkably, expression of several proliferation-promoting factors including the proto-oncogene FoxM1 and its targets are induced by LXR-S196A. This is consistent with increased proliferation of plaque-resident cells in M-S196ALdlr-KO mice. Moreover, disrupted LXR phosphorylation increases expression of phagocytic molecules resulting in increased apoptotic cell removal by macrophages, explaining the reduced necrotic cores. Finally, the macrophage transcriptome promoted by LXR-S196A under dietary perturbation is markedly distinct from that revealed by LXR ligand activation, highlighting the singularity of this post-translational modification. Overall, our findings demonstrate that LXR phosphorylation at S196 is an important determinant of atherosclerotic plaque development through selective changes in gene transcription that affect multiple pathways.

physiology↗