Citations 5
Author response: Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD)
Zhang, Ting , Ambrodji, Alisa , Huang, Huixing, Etheridge, Amy S. , Schmidt, Remington E. , Bembenek, Brianna M. , Temesgen, Zoey B., Innocenti, Federico , Diasio, Robert B. , Largiadèr, Carlo R. , Offer, Steven M. , Largiadèr, Carlo R , Offer, Steven M , Bouchonville, Kelly J. , Wang, Zhiquan , Stroka, Deborah
No container title available | April 30, 2024 | Volume: No volume available | Issue: No issue available | Pages: No page available
Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD)
Zhang, Ting , Ambrodji, Alisa , Huang, Huixing, Etheridge, Amy S. , Schmidt, Remington E. , Bembenek, Brianna M. , Temesgen, Zoey B., Innocenti, Federico , Diasio, Robert B. , Bouchonville, Kelly J. , Wang, Zhiquan , Stroka, Deborah , Largiadèr, Carlo R. , Offer, Steven M.
eLife | April 30, 2024 | Volume: 13 | Issue: No issue available | Pages: No page available
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD)
Zhang, Ting , Ambrodji, Alisa , Huang, Huixing, Bouchonville, Kelly J. , Etheridge, Amy S. , Schmidt, Remington E. , Bembenek, Brianna M. , Temesgen, Zoey B., Wang, Zhiquan , Innocenti, Federico , Diasio, Robert B. , Stroka, Deborah , Largiadèr, Carlo R. , Offer, Steven M. , Wang, Zhiquan
No container title available | April 16, 2024 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD)
Ambrodji, Alisa , Huang, Huixing, Etheridge, Amy S. , Schmidt, Remington E. , Bembenek, Brianna M. , Temesgen, Zoey B., Wang, Zhiquan , Innocenti, Federico , Diasio, Robert B. , Zhang, Ting , Bouchonville, Kelly J. , Stroka, Deborah , Largiadèr, Carlo R. , Offer, Steven M. , Wang, Zhiquan
No container title available | January 10, 2024 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD)
Zhang, Ting , Ambrodji, Alisa , Huang, Huixing, Bouchonville, Kelly J. , Etheridge, Amy S. , Schmidt, Remington E. , Bembenek, Brianna M. , Temesgen, Zoey B., Wang, Zhiquan , Innocenti, Federico , Diasio, Robert B. , Temesgen, Zoey B , Stroka, Deborah , Largiadèr, Carlo R , Offer, Steven M , Largiadèr, Carlo R. , Offer, Steven M. , Wang, Zhiquan
eLife | January 10, 2024 | Volume: 13 | Issue: No issue available | Pages: No page available
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.