Biology Reference
In-Depth Information
Not predicted from premicroarray studies was a set of genes upregulated
by TH in every tissue examined, such as TR
b
, TH/bZIP, KLF9, NFI-X2, all
of which are transcription factors. This common set of development genes in
organs with different responses to TH, from cell death to cell proliferation,
suggests that it is quite likely that a combination of organ-specific TH-
regulated early genes, especially downregulated ones, and organ-specific re-
sponses to the changes in common TH-regulated genes dictates organ-specific
metamorphic changes. Thus, an important area of interest will be to deter-
mine the downstream targets of the common early regulated genes.
Additional unexpected findings from the microarray analyses are the total
number of TH-response genes involved, well above 1000 genes as compo-
nents of the TH gene regulation cascade and well over 200 direct response
genes. Our bias in understanding the molecular mechanisms of direct induc-
tion versus repression of gene expression by TH did not prepare us for the
identification of equivalent numbers of up- and downregulated genes.
Finally, a newly uncovered complexity to the gene regulation cascade,
namely, the web of intra- and extracellular signaling pathways induced by
TH, was not initially predicted but undoubtedly contributes to the outcome
of tissue-specific responses to TH. These novel and important findings about
the number and identity of TH-induced genes and their spatial and temporal
changes during tadpole development secures the value of microarray studies
on frog metamorphosis.
Not only developmental studies but also studies on endocrine disruption
have benefitted from microarray analyses. Based on morphological or phys-
iological endpoints, many chemicals appear to interfere with endocrine
physiology. However, as hormonal control of development and homeostasis
is complex and as hormone systems can interact with each other, the mech-
anisms of action of a given chemical are not often obvious. Identifying the
global pattern of altered gene regulation of an endocrine disruptor gives in-
sight into how that chemical is acting and interacting with the endocrine
system. Another use of microarray in endocrine disruption studies lies in
the search for biomarkers of TH endocrine disruption. A useful biomarker
requires particular properties of its response to TH, namely it must be a sen-
sitive and robust marker of TH signaling. Global analysis of potential genes
allows one to select the most appropriate gene or small set of genes from the
large group of TH-response genes that may not all have desirable fold-
change levels or expression kinetics. This strategy for identifying suitable
genes has also been employed in development studies where larval- versus
adult-specific genes have been found for intestinal epithelium and skin and
