This study investigates the role of intragenic DNA methylation in regulating alternative promoters. The authors generated a high-resolution methylome map of human brain frontal cortex gray matter using two complementary next-generation sequencing approaches: MeDIP-seq and MRE-seq. They found that the majority of methylated CpG islands (CGIs) were located in intragenic and intergenic regions, with less than 3% of CpG islands in 5′ promoters being methylated. Intragenic CGIs were more frequently methylated than 5′ promoter CGIs, and this pattern was conserved in mouse tissues. The authors further demonstrated that intragenic methylation regulates alternative promoter activity *in vitro* and *in vivo* using the *SHANK3* locus as a model. They identified two conserved intragenic CGIs (ECR22 and ECR32) that function as alternative promoters, which are expressed differentially within a single cell type from distinct brain regions. These findings suggest that intragenic DNA methylation plays a significant role in regulating cell context-specific alternative promoters in gene bodies.This study investigates the role of intragenic DNA methylation in regulating alternative promoters. The authors generated a high-resolution methylome map of human brain frontal cortex gray matter using two complementary next-generation sequencing approaches: MeDIP-seq and MRE-seq. They found that the majority of methylated CpG islands (CGIs) were located in intragenic and intergenic regions, with less than 3% of CpG islands in 5′ promoters being methylated. Intragenic CGIs were more frequently methylated than 5′ promoter CGIs, and this pattern was conserved in mouse tissues. The authors further demonstrated that intragenic methylation regulates alternative promoter activity *in vitro* and *in vivo* using the *SHANK3* locus as a model. They identified two conserved intragenic CGIs (ECR22 and ECR32) that function as alternative promoters, which are expressed differentially within a single cell type from distinct brain regions. These findings suggest that intragenic DNA methylation plays a significant role in regulating cell context-specific alternative promoters in gene bodies.