Stress and glucocorticoid receptor transcriptional programming in time and space: Implications for the brain-gut axis

Abstract

Background: Chronic psychological stress is associated with enhanced abdominal pain and altered intestinal barrier function that may result from a perturbation in the hypothalamic-pituitary-adrenal (HPA) axis. The glucocorticoid receptor (GR) exploits diverse mechanisms to activate or suppress congeneric gene expression, with regulatory variation associated with stress-related disorders in psychiatry and gastroenterology.

Purpose: During acute and chronic stress, corticotropin-releasing hormone drives secretion of adrenocorticotropic hormone from the pituitary, ultimately leading to the release of cortisol (human) and corticosterone (rodent) from the adrenal glands. Cortisol binds with the GR in the cytosol, translocates to the nucleus, and activates the NR3C1 (nuclear receptor subfamily 3, group C, member 1 [GR]) gene. This review focuses on the rapidly developing observations that cortisol is responsible for driving circadian and ultradian bursts of transcriptional activity in the CLOCK (clock circadian regulator) and PER (period circadian clock 1) gene families, and this rhythm is disrupted in major depressive disorder, bipolar disorder, and stress-related gastrointestinal and immune disorders. Glucocorticoid receptor regulates different sets of transcripts in a tissue-specific manner, through pulsatile waves of gene expression that includes occupancy of glucocorticoid response elements located within constitutively open spatial domains in chromatin. Emerging evidence supports a potentially pivotal role for epigenetic regulation of how GR interacts with other chromatin regulators to control the expression of its target genes. Dysregulation of the central and peripheral GR regulome has potentially significant consequences for stress-related disorders affecting the brain-gut axis.

Keywords: CLOCK genes; chronic stress; epigenomics; intestinal barrier function; irritable bowel syndrome; mental health disorders.

Figure 1

The glucocorticoid receptor, regulation of gene expression, and its clinical consequences. (A) The glucocorticoid receptor (GR) and regulation of the CLOCK gene family. This pathway contributes to regulation of circadian rhythmicity, and is driven by the hypothalamic-pituitary-adrenal axis and metabolic inputs from liver. Of all the thousands of genes whose expression is regulated by the GR, the most highly regulated include members of the CLOCK gene family such as PER1 (33). Products of ARNTL and CLOCK form a heterodimer that acts a transcription factor and binds to the E-box (E) in the promoter of other GR-regulated CLOCK and related genes, including CRY, PER, NR1D1, and RORA. In general, both CRY and PER genes are expressed in a circadian manner, acting either by repressing the CLOCK:ARNTL heterodimer, or blocking GR from binding to the GR response element (GRE) sequence. This latter mechanism is described in the section: GR rhythmicity, dysregulation, and the brain–gut axis. NR1D1 and RORA form a heterodimer that acts as a transcription factor that binds to the RORE sequence that is located in genes such as ARNTL. The ARNTL protein also acts independently of its role as a transcription factor to mediate translational control of specific proteins in a circadian manner (118). (B) Overview of results from the NIH Roadmap Epigenomics Mapping Consortium. Chromosomes are located in chromatin-bound territories in the nucleus. Euchromatin is characterized by DNase 1 hypersensitivity and specific combinations of histone marks that define active genomic regulatory elements, such as promoters H3K4me3 and H3K27ac, and enhancers H3K4me1 and H3K27ac. An enhancer can either increase or decrease transcription. Recent research demonstrates that, in brain, the DNA sequence CAC is a common site of methylation, in contrast to other tissues where CpG is most often methylated. Also, in brain, 5-hydroxymethylcytosine (5hmC), a reactive species, is common. In contrast, in the periphery, methylcytosine (hmC) is common (76). (C) Chronic and/or early life stress appear to lead to alteration of chromatin and allele-biased gene expression, concomitant with psychiatric disorders and comorbid conditions including irritable bowel syndrome. In such cases, allele skewing of transcription (21, 22) is most likely a consequence of epigenetic alterations arising from environmental adversity that contributes to a variety of stress-related disorders distinct from parental imprinting (29, 30). POLR2A polymerase (RNA) II (DNA directed) polypeptide A, 220kDa is a highly conserved, ubiquitously expressed gene that encodes the largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes and, therefore, plays an important role in gene transcription. Allelic imbalance refers to differential expression of the maternal vs paternal allele. POLR2A, DNA-dependent RNA polymerase II; H3K4me3, histone H3 trimethyl Lys4; H3K27ac, histone H3 Lys27 acetylation; H3Kme1, histone H3 monomethyl Lys4. of methylation, in contrast to other tissues where CpG is most often methylated. Also, in brain, 5-hydroxymethylcytosine (5hmC), a reactive species, is common. In contrast, in the periphery, methylcytosine (hmC) is common (76). (C) Chronic and/or early life stress appear to lead to alteration of chromatin and allele-biased gene expression, concomitant with psychiatric disorders and comorbid conditions including irritable bowel syndrome. In such cases, allele skewing of transcription (21, 22) is most likely a consequence of epigenetic alterations arising from environmental adversity that contributes to a variety of stress-related disorders distinct from parental imprinting (29, 30). POLR2A polymerase (RNA) II (DNA directed) polypeptide A, 220kDa is a highly conserved, ubiquitously expressed gene that encodes the largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes and, therefore, plays an important role in gene transcription. Allelic imbalance refers to differential expression of the maternal vs paternal allele. POLR2A, DNA-dependent RNA polymerase II; H3K4me3, histone H3 trimethyl Lys4; H3K27ac, histone H3 Lys27 acetylation; H3Kme1, histone H3 monomethyl Lys4.