Estrogen Represses Target Genes through Epigenetic Modification of Proximal and Distal Elements
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The Ohio State University / OhioLINK
2010
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu12677603422021-08-03T05:58:46Z Estrogen Represses Target Genes through Epigenetic Modification of Proximal and Distal Elements Rodriguez, Benjamin Andrew Genetics Science <p>Estrogens and their receptors are important in human development, physiology, and disease. At the molecular level, 17β-estradiol (E2) promotes breast tumorigenesis and cancer progression by altering the transcriptional activity and expression profile of target genes. While more than two decades of research have focused on Estrogen Receptor (ER) target gene activation, transcriptional repression by ERs is less well understood. Here we have investigated the different epigenetic mechanisms by which E2 represses the expression of two target genes, HOXB13 and CDKN1C. Both genes possess promoter CpG islands, show strong evolutionary conservation in vertebrates, play important roles in development and control of cell growth, and are downregulated in many human cancers.</p><p>The expression of HOXB13 and CDKN1C are both suppressed by the activation of estrogen signaling in ERalpha-positive breast cancer cells. This suppression is abrogated by treatment with the anti-estrogen 4-hydroxytamoxifen (4-OHT) treatment, indicating it is ERalpha-mediated. Epigenetic silencing of HOXB13 occurs in part as the result of aberrant promoter CpG island hypermethylation. Promoter hypermethylation of HOXB13 is more frequently observed in ERalpha-positive patients and is associated with shorter disease-free survival (P = 0.029). CDKN1C is an imprinted gene regulated by the 11p15.5 KCNQ1OT1-DMR Imprinting Control Region (ICR). Epigenetic silencing of CDKN1C occurs not through promoter hypermethylation, but in part as the result of demethylation at the distal 11p15.5 ICR caused by selective genetic loss of the methylated allele. Loss of methylation was further confirmed in primary tumors.</p> <p>Several lines of evidence suggest estrogen signaling suppresses CDKN1C through epigenetic mechanisms. Transcriptional repression occurs in conjunction with repressive chromatin alterations at the CDKN1C locus and the recruitment of transcription regulator proteins both to the gene and to the distal 11p15.5 ICR. Activation of estrogen signaling also induced expression of KCNQ1OT1, the non-coding RNA involved in maintaining imprinting of the 11p15.5 domain. These findings suggest estrogen signaling can regulate CDKN1C through the modulation of 11p15.5 ICR activity. CDKN1C is also associated with a cis-encoded natural antisense transcript, CDKN1C-AS, that is induced by estrogen signaling under cellular conditions where DNA methyltransferase and Histone deacetylase activity are inhibited. Forced expression of CDKN1C-AS induces silencing of endogenous CDKN1C in trans. Sense and antisense CDKN1C expression are associated with different prognostic outcomes in breast carcinoma patients.</p><p>In conclusion, we investigated two different epigenetic mechanisms by which E2 represses the expression of target genes. Both HOXB13 and CDKN1C are suppressed by the activation of estrogen signaling in ERalpha-positive breast cancer cells. Epigenetic silencing of HOXB13 occurs in part as the result of promoter hypermethylation; this aberrant event occurs most frequently in ERalpha-positive patients. Epigenetic silencing of CDKN1C occurs in part as the result of loss of differential methylation at the distal 11p15.5 ICR and also through modulation of ICR activity initiated by estrogen signaling. HOXB13 promoter hypermethylation as well as sense and antisense CDKN1C transcription are associated with clinical outcome in breast cancer patients.</p> 2010-08-23 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1267760342 http://rave.ohiolink.edu/etdc/view?acc_num=osu1267760342 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Genetics Science |
| spellingShingle |
Genetics Science Rodriguez, Benjamin Andrew Estrogen Represses Target Genes through Epigenetic Modification of Proximal and Distal Elements |
| author |
Rodriguez, Benjamin Andrew |
| author_facet |
Rodriguez, Benjamin Andrew |
| author_sort |
Rodriguez, Benjamin Andrew |
| title |
Estrogen Represses Target Genes through Epigenetic Modification of Proximal and Distal Elements |
| title_short |
Estrogen Represses Target Genes through Epigenetic Modification of Proximal and Distal Elements |
| title_full |
Estrogen Represses Target Genes through Epigenetic Modification of Proximal and Distal Elements |
| title_fullStr |
Estrogen Represses Target Genes through Epigenetic Modification of Proximal and Distal Elements |
| title_full_unstemmed |
Estrogen Represses Target Genes through Epigenetic Modification of Proximal and Distal Elements |
| title_sort |
estrogen represses target genes through epigenetic modification of proximal and distal elements |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2010 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1267760342 |
| work_keys_str_mv |
AT rodriguezbenjaminandrew estrogenrepressestargetgenesthroughepigeneticmodificationofproximalanddistalelements |
| _version_ |
1719428818672812032 |