CpG content contributes to tissue-resident macrophage enhancer selection

Bojcsuk, Dóra and Varga, Zsófia and Kolostyák, Zsuzsanna and Tzerpos, Petros and Caballero-Sanchez, Noemi and Cseh, Tímea and Patsalos, Andreas and Czimmerer, Zsolt and Nagy, László and Nagy, Gergely (2026) CpG content contributes to tissue-resident macrophage enhancer selection. NUCLEIC ACIDS RESEARCH, 54 (16). No. gkag824. ISSN 0305-1048 (print); 1362-4962 (online)

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Abstract

Tissue-resident macrophages acquire specialized identities through transcription factor networks operating in distinct chromatin environments. Early growth response 2 (EGR2) contributes both to alveolar macrophage identity and to interleukin (IL)-4-driven polarization of bone marrow-derived macrophages, yet the regulatory principles enabling its function across these contexts remain unclear. By integrating RNA-seq and ATAC-seq data from wild-type and Egr2-deficient macrophages, we show that macrophage identity is constrained by DNA methylation-dependent cis-regulatory landscapes. Alveolar macrophage-specific enhancers are predominantly CpG rich and hypomethylated, a feature shared with additional tissue-resident macrophage populations, whereas bone marrow-derived macrophage-accessible regulatory regions are largely CpG poor. Although IL-4 induces EGR2 together with KLF4 and DEC1 in bone marrow-derived macrophages, this transcription factor module fails to engage CpG-rich enhancers, indicating that the bone marrow-derived macrophage regulatory network lacks additional alveolar macrophage-specific components required for their activation. These findings identify CpG content as a determinant of enhancer competence and provide a mechanistic explanation for the context-dependent activity of EGR2 in macrophages, placing macrophage plasticity under the control of sequence-encoded epigenetic constraints.

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