Biology Reference
In-Depth Information
genes responding to CORT or TH only without influence from the other
hormone. Thus, microarray studies are well suited to the goal of identifying
biomarkers for developmental as well as endocrine disruption studies.
The wealth of knowledge obtained using microarray experiments has
come despite some technical issues associated with the technique. The high
variability among workers in terms of genes identified as TH-regulated
stems in part from the microarray methods and also in part from different
rearing and TH treatment conditions among studies. These interstudy dis-
crepancies indicate that microarray data are not definitive but rather indic-
ative of important genes and pathways. Another issue is that currently many
elements on the microarrays have no ascribed function because they are
ESTs representing nonconserved 3 0 UTRs or hypothetical proteins with
low or no homology to a mammalian sequence, giving little information
about gene function. Improvements in gene annotation and genomics
should refine the complement of known response genes.
While much has been learned about gene regulation cascades, much is
still left to understand. Noncoding RNAs are now believed to have a major
impact on gene regulation and undoubtedly contribute to tissue-specific TH
responses. Differential expression of noncoding RNAs due to TH can be
analyzed by microarray technology but thus far have not been examined.
Another gap in our knowledge is distinguishing cause from effect in the gene
regulation cascade. Microarray analysis provides molecular correlations with
cellular and histological changes. In many cases cause and effect relationships
can be inferred, such as upregulation of proteases with ECM degradation or
upregulation of cell cycle genes with cell proliferation. However, it is often
difficult to sort out causes versus effect underlying control of the tissue-
specific gene regulation cascades. Determining the web of interactions
starting with direct response genes to how they interact with already present
tissue-specific transcription factors and TH-indirect response genes may
benefit from additional microarray analyses using transgenic-inducible over-
expression of TH-direct response transcription factors but likely other re-
search approaches as well. Another important consideration is that the
relationship between mRNA levels, as detected by microarray analysis,
and the cognate protein levels for most genes is not currently known.
The relationship between protein levels and their activity levels altered by
posttranslational modifications is also not known. Thus, identifying TH-
induced genes is a critical first step, but other types of research, including
proteomics and functional studies, are required to elucidate protein levels
and the downstream effects of protein activity.
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