Transcriptional regulation of corticotropin-releasing hormone gene in stress response

Abstract

As a central player of the hypothalamic-pituitary-adrenal (HPA) axis, the corticotropin -releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) determine the state of HPA axis and play a key role in stress response. Evidence supports that during stress response the transcription and expression of CRH was finely tuned, which involved cis-element-transcriptional factor (TF) interactions and epigenetic mechanisms. Here we reviewed recent progress in CRH transcription regulation from DNA methylation to classic TFs regulation, in which a number of paired receptors were involved. The imbalance of multiple paired receptors in regulating the activity of CRH neurons indicates a possible molecular network mechanisms underlying depression etiology and directs novel therapeutic strategies of depression in the future.

Keywords: Corticotropin-releasing hormone; Paraventricular nucleus; Stress; Transcriptional factors.

Fig. 1

Schematic diagram for CRH transcriptional regulation. A, CRH gene consists two exons and one intron. Most DNA methylation sites (CpG islands) and most cis-elements (positive, solid box; negative, dashed box) locate in the promoter region except NRSE, which is in the first intron. MicroRNA binding sites are predicted to locate in the 3′ untranslated region (UTR). B, Regarding to multiple paired receptors involved in the transcriptional regulation of CRH, after binding with the ligand, the receptors translocate to the nucleus and bind to the specific elements (positive, solid box; negative, dashed box) in the promoter region of CRH and regulate CRH mRNA expression. Abbreviations: AR, Androgen receptor; ER, Estrogen receptor; GR, Glucocorticoid receptor; MR, Mineralocorticoid receptor; RAR, Retinoic acid receptor; RXR, Retinoic X receptor; ARE, androgen response element; ERE, estrogen response element; GRE, glucocorticoid response element; MRE, mineralocorticoid response element; RARE, retinoic acid response element; NRSE, neuron-restrictive silencing element.