Abstract
Previous studies indicate that Chinese indigenous pig breeds demonstrate distinct pattern of glucocorticoid receptor (GR) expression, which is associated with their unique growth and metabolic phenotypes. Here we sought to unravel the transcriptional mechanisms underlying the breed-specific hepatic GR expression in preweaning Chinese Erhualian (EHL) and Western Large White (LW) piglets. Total GR mRNA and the predominant GR mRNA variant 1–9/10 were expressed significantly higher in EHL compared with LW piglets (P<0.01), which was associated with more enriched histone H3 acetylation on 1–9/10 promoter (P<0.05). Nuclear content of transcription factor specificity protein 1 (Sp1) was significantly lower in EHL piglets, yet its binding to GR 1–9/10 promoter was significantly higher in EHL piglets, as revealed by chromatin immunoprecipitation assays. Although p53 binding to GR promoter 1–9/10 did not differ between breeds, expression of p53 mRNA and protein, as well as its binding to Sp1, were significantly higher in EHL piglets. Moreover, p53 activator doxorubicin significantly enhanced GR 1–9/10 promoter activity in HepG2 cells at 100 nM, which was associated with significantly higher protein content of p53 and GR. Sp1 inhibitor, mithramycin A, significantly inhibited (P<0.05) the basal activity of GR promoter 1–9/10 and completely blocked doxorubicin -induced activation of GR promoter 1–9/10. These data indicate that higher hepatic GR expression in EHL piglets attributes mainly to the enhanced transcription of GR promoter 1–9/10, which is achieved from breed-specific interaction of p53 and Sp1 on porcine GR 1–9/10 promoter.
Highlights
Glucocorticoid receptor (GR) mediates most functions of glucocorticoids and plays indispensable roles in almost all aspects of life including growth and differentiation, energy homeostasis and obesity, as well as immunity and stress responses [1,2]
We reported recently that 59-untranslated GR exon 1 mRNA variants 1–4 and 1–5, as well as the total GR mRNA are expressed in a breed-dependent manner in the liver of newborn piglets, Large White (LW) showing significantly higher expression compared with Erhualian (EHL), a Chinese indigenous breed [17]
This finding is in line with a recently published paper showing that exon 1-9/10 is the predominant variant in porcine liver which accounts for about 65% of total GR mRNA [26]
Summary
Glucocorticoid receptor (GR) mediates most functions of glucocorticoids and plays indispensable roles in almost all aspects of life including growth and differentiation, energy homeostasis and obesity, as well as immunity and stress responses [1,2]. Expression of GR gene is controlled in a temporal, spatial and tissue-specific manner by sophisticated mechanisms at different levels, including chromatin condensation, transcription initiation, alternative RNA splicing, mRNA stability and others Among all these regulatory mechanisms, the progression of transcriptional regulation is known to play a major role [8,9,10]. We reported recently that 59-untranslated GR exon 1 mRNA variants 1–4 and 1–5, as well as the total GR mRNA are expressed in a breed-dependent manner in the liver of newborn piglets, Large White (LW) showing significantly higher expression compared with Erhualian (EHL), a Chinese indigenous breed [17] This breed difference contradicts with the previous findings that Chinese pigs usually express higher GR compared to Western pig breeds in hippocampus [1], liver [2] and muscle [3] at later ages after weaning.
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