GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE317nnn/GSE317131/primaryOK200GenomicsMus musculusGenome binding/occupancy profiling by high throughput sequencing Expression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE317131GEOGSEfalseCpG content determines tissue-resident macrophage enhancer selectionTissue-resident macrophages (TRMs) acquire specialized identities through transcription factor (TF) networks operating in distinct chromatin environments. Early growth response 2 (EGR2) contributes both to alveolar macrophage (AM) identity and to interleukin (IL)-4-driven polarization of bone marrow-derived macrophages (BMDMs), 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. AM-specific enhancers are predominantly CpG-rich and hypomethylated, a feature shared with additional TRM populations, whereas BMDM-accessible regulatory regions are largely CpG-poor. Although IL-4 induces EGR2 together with KLF4 and DEC1 in BMDMs, this TF module fails to engage CpG-rich enhancers, indicating that the BMDM regulatory network lacks additional AM-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.2026/07/28GSE317131GSM9465532GSM9465543GSM9465542GSM9465531GSM9465534GSM9465545GSM9465544GSM9465533GSM9465547GSM9465536GSM9465535GSM9465546GSM9465538GSM9465527GSM9465537GSM9465548GSM9465541GSM9465530GSM9465540GSM9465529GSM9465539GSM94655281905730172317131Mus musculus