Promoter CpG methylation of Hoxa-10 and Hoxa-11 in mouse uterus not altered upon neonatal diethylstilbestrol exposure
2001 Study Abstract
Mouse abdominal B-like Hoxa genes are expressed and functionally required in the developing reproductive tracts. Mice lacking either Hoxa-10 or Hoxa-11, two of the AbdB Hoxa genes, exhibit abnormal uterine development similar to that induced by in utero diethylstilbestrol (DES) exposure.
Indeed, uterine Hoxa10 and Hoxa11 expression is potently repressed by perinatal DES exposure, providing a potential molecular mechanism for DES-induced reproductive tract malformations.
We have shown previously that DES can permanently alter uterine lactoferrin gene expression through modulation of the lactoferrin promoter methylation pattern. Here we ask whether a similar mechanism also functions to deregulate uterine Hoxa-10 or Hoxa-11 expression during neonatal DES exposure.
We mapped the Hoxa-10 promoter by cloning a 1.485 kb DNA fragment 5′ of the Hoxa-10 exon1a. A 5′ rapid amplification of cDNA ends (RACE) experiment revealed a transcription start site for the a10-1 transcript.
Functional analysis of the proximal 200-bp sequences demonstrated significant promoter activity, confirming the location of the Hoxa-10 promoter. Moreover, methylation assays performed on eight CpGs in Hoxa-10 and 19 CpGs in Hoxa-11 proximal promoters demonstrated that all these CpGs were highly unmethylated in both control and DES-dosed mice from postnatal day 5 to day 30. Significant methylation around Hoxa10 and Hoxa11 promoters was only observed in DES-induced uterine carcinomas in 18-mo-old mice.
Our results suggest that DES-induced downregulations of Hox-a10 or Hox-a11 gene expression are not associated with methylation changes in their proximal promoters and that gene imprinting by developmental DES exposure may be a gene-specific phenomenon.
Sources and more information
- Promoter CpG methylation of Hox-a10 and Hox-a11 in mouse uterus not altered upon neonatal diethylstilbestrol exposure, Molecular carcinogenesis, NCBI PubMed PMID : 11746833, 2001 Dec.
- Featured image credit .researchgate.