Organisms respond to environmental insults by inducing detoxification and cellular repair genes. Gene induction is controlled by sequence-specific transcription factors (TFs) that bind to response elements in promoters of the inducible genes, and recruit transcriptional coregulators to stimulate RNA polymerase II transcription. Exposure of Caenorhabditis elegans to the toxic heavy metal cadmium induces a robust gene expression response, which is partially dependent on
mdt-15, a subunit of the Mediator transcriptional coregulator complex; however, additional molecular factors that partner with
mdt-15 in this response remain unknown. Here, we show that the
elt-2 GATA-family TF, two GATA-site response elements, and the Mediator subunit
cdk-8 are also required for cadmium-inducible gene expression. Furthermore, we identify regulatory interactions between
elt-2,
cdk-8, and
mdt-15 in vivo. Microarray profiling revealed significant overlap between
cdk-8-dependent genes and cadmium-responsive genes. In line with this,
cdk-8 is required for cadmium-induced gene expression, e.g.
cdr-1 (cadmium-responsive 1),
mtl-1 and
mtl-2 (metallothioneins). Mediator subunit
mdt-15 is known to activate these cadmium-inducible genes, indicating that
cdk-8 and
mdt-15 converge on common gene targets. The
cdr-1 promoter contains several putative regulatory elements that may be bound by TFs. By mutating these elements or RNAi depleting their putative TF partners, we showed that only two GATA elements and the corresponding
elt-2 GATA-family TF were required for cadmium-induced
cdr-1 promoter activation. To test if
cdk-8,
mdt-15, and
elt-2 form a pathway regulating cadmium-inducible transcription, we performed genetic epistasis analysis. Loss of
cdk-8,
mdt-15, or
elt-2 alone caused cadmium sensitivity in C. elegans. Cadmium sensitivity upon combined loss of
mdt-15 and
elt-2 could not be assessed, as these worms exhibited severe developmental delay; therefore,
mdt-15 and
elt-2 appear to act in parallel to promote an unidentified developmental pathway. Combined loss of
cdk-8 and
elt-2 did not significantly enhance cadmium sensitivity compared to each single mutant; therefore,
cdk-8 and
elt-2 form a pathway to promote cadmium resistance. Overall, this study identifies a new transcriptional regulatory pathway governing an inducible transcription response to the toxic heavy metal cadmium.