TY - JOUR
T1 - A modular system of DNA enhancer elements mediates tissue-specific activation of transcription by high dietary zinc in C. elegans
AU - Roh, Hyun Cheol
AU - Dimitrov, Ivan
AU - Deshmukh, Krupa
AU - Zhao, Guoyan
AU - Warnhoff, Kurt
AU - Cabrera, Daniel
AU - Tsai, Wendy
AU - Kornfeld, Kerry
N1 - Publisher Copyright:
© 2015 The Author(s).
PY - 2015/1/30
Y1 - 2015/1/30
N2 - Zinc is essential for biological systems, and aberrant zinc metabolism is implicated in a broad range of human diseases. To maintain homeostasis in response to fluctuating levels of dietary zinc, animals regulate gene expression; however, mechanisms that mediate the transcriptional response to fluctuating levels of zinc have not been fully defined. Here, we identified DNA enhancer elements that mediate intestine-specific transcriptional activation in response to high levels of dietary zinc in C. elegans. Using bioinformatics, we characterized an evolutionarily conserved enhancer element present in multiple zinc-inducible genes, the high zinc activation (HZA) element. The HZA was consistently adjacent to a GATA element that mediates expression in intestinal cells. Functional studies using transgenic animals demonstrated that this modular system of DNA enhancers mediates tissue-specific transcriptional activation in response to high levels of dietary zinc. We used this information to search the genome and successfully identified novel zinc-inducible genes. To characterize the mechanism of enhancer function, we demonstrated that the GATA transcription factor ELT-2 and the mediator subunit MDT-15 are necessary for zinc-responsive transcriptional activation. These findings define new mechanisms of zinc homeostasis and tissue-specific regulation of transcription.
AB - Zinc is essential for biological systems, and aberrant zinc metabolism is implicated in a broad range of human diseases. To maintain homeostasis in response to fluctuating levels of dietary zinc, animals regulate gene expression; however, mechanisms that mediate the transcriptional response to fluctuating levels of zinc have not been fully defined. Here, we identified DNA enhancer elements that mediate intestine-specific transcriptional activation in response to high levels of dietary zinc in C. elegans. Using bioinformatics, we characterized an evolutionarily conserved enhancer element present in multiple zinc-inducible genes, the high zinc activation (HZA) element. The HZA was consistently adjacent to a GATA element that mediates expression in intestinal cells. Functional studies using transgenic animals demonstrated that this modular system of DNA enhancers mediates tissue-specific transcriptional activation in response to high levels of dietary zinc. We used this information to search the genome and successfully identified novel zinc-inducible genes. To characterize the mechanism of enhancer function, we demonstrated that the GATA transcription factor ELT-2 and the mediator subunit MDT-15 are necessary for zinc-responsive transcriptional activation. These findings define new mechanisms of zinc homeostasis and tissue-specific regulation of transcription.
UR - http://www.scopus.com/inward/record.url?scp=84945180435&partnerID=8YFLogxK
U2 - 10.1093/nar/gku1360
DO - 10.1093/nar/gku1360
M3 - Article
C2 - 25552416
AN - SCOPUS:84945180435
SN - 0305-1048
VL - 43
SP - 803
EP - 816
JO - Nucleic acids research
JF - Nucleic acids research
IS - 2
ER -