This study investigates the regulation of the mouse *Scgb3a1* gene, which encodes a secretory protein with tumor suppressor functions, primarily expressed in the lung and trachea. The authors demonstrate that the gene is regulated by the ubiquitous transcription factor NF-Y, which binds to "CCAAT" binding sites located at -425 to -429 bp and -498 to -502 bp from the transcription start site. However, the effect of PU-box binding protein on transcriptional activation is minimal compared to NF-Y, suggesting that NF-Y is a more critical factor for *Scgb3a1* gene transcription. Despite NF-Y's ubiquitous nature, *Scgb3a1* is highly expressed only in the lung and mtCC cells, not in other tissues. Gene methylation analysis reveals that within 600 bp of the *Scgb3a1* gene promoter region, there are nine CpG methylation sites, with two CpGs closest to the transcription start site being unmethylated in tissues/cells expressing *Scgb3a1*. These findings suggest that CpG methylation plays a role in the tissue-specific expression of the *Scgb3a1* gene.This study investigates the regulation of the mouse *Scgb3a1* gene, which encodes a secretory protein with tumor suppressor functions, primarily expressed in the lung and trachea. The authors demonstrate that the gene is regulated by the ubiquitous transcription factor NF-Y, which binds to "CCAAT" binding sites located at -425 to -429 bp and -498 to -502 bp from the transcription start site. However, the effect of PU-box binding protein on transcriptional activation is minimal compared to NF-Y, suggesting that NF-Y is a more critical factor for *Scgb3a1* gene transcription. Despite NF-Y's ubiquitous nature, *Scgb3a1* is highly expressed only in the lung and mtCC cells, not in other tissues. Gene methylation analysis reveals that within 600 bp of the *Scgb3a1* gene promoter region, there are nine CpG methylation sites, with two CpGs closest to the transcription start site being unmethylated in tissues/cells expressing *Scgb3a1*. These findings suggest that CpG methylation plays a role in the tissue-specific expression of the *Scgb3a1* gene.