Temporal Pole Responds to Subtle Changes in Local Thyroid Hormone Signaling

Abstract

To study thyroid hormone (TH) signaling in the human brain, we analyzed published microarray data sets of the temporal pole (Brodmann area 38) of 19 deceased donors. An index of TH signaling built on the expression of 19 well known TH-responsive genes in mouse brains (T3S+) varied from 0.92 to 1.1. After Factor analysis, T3S+ correlated independently with the expression of TH transporters (MCT8, LAT2), TH receptor (TR) beta and TR coregulators (CARM1, MED1, KAT2B, SRC2, SRC3, NCOR2a). Unexpectedly, no correlation was found between T3S+ vs DIO2, DIO3, SRC1, or TRα. An unbiased systematic analysis of the entire transcriptome identified a set of 1649 genes (set #1) with strong positive correlation with T3S+ (r > 0.75). Factor analysis of set #1 identified 2 sets of genes that correlated independently with T3S+, sets #2 (329 genes) and #3 (191 genes). When processed through the Molecular Signatures Data Base (MSigDB), both sets #2 and #3 were enriched with Gene Ontology (GO)-sets related to synaptic transmission and metabolic processes. Ranking individual human brain donors according to their T3S+ led us to identify 1262 genes (set #4) with >1.3-fold higher expression in the top half. The analysis of the overlapped genes between sets #1 and #4 resulted in 769 genes (set #5), which have a very similar MSigDB signature as sets #2 and #3. In conclusion, gene expression in the human temporal pole can be assessed through T3S+ and fluctuates with subtle variations in local TH signaling.

Keywords: brain; gene expression profile; hypothyroidism; thyroid hormones.

Figure 1.

TH signaling in the brain depends on a triad of elements that regulate TH action: (i) transmembrane transporters, ie, OATPs, MCTs, and LATs, that mediate passage of both T4 and T3 through the blood brain barrier and local cells; (ii) deiodinases metabolize TH locally, ie, DIO2 and DIO3, respectively activating and inactivating TH; (iii) TRs, mostly TRα and to a lesser extent TRβ. In the present in silico studies, microarray data previously derived from 19 human Brodmann area 38 (temporal pole) samples was used to generate a T3 positive signaling index (T3S+).

Figure 2.

Correlation analysis between T3S+ and the components included at the Factors 1 and 2 that reached statistical significance in Factor Analysis. TH transporters LAT2 (A), MCT8 (B), TH receptor TRβ (C), coactivators CARM1 (D), KAT2B (E), MED1 (F), SRC-2 (G), and SRC-3 (H), and corepressor NCOR2 (I). Statistical significance is shown in each graph as well as Spearman’s correlation coefficient (r).

Figure 3.

Heat map indicating the top 50 genes enriched in temporal pole samples when 2 subgroups of donors: lower (LT3S+) vs higher (HT3S+) were processed through GSEA.