Histone deacetylase 1 (HDAC1) participates in the down-regulation of corticotropin releasing hormone gene (crh) expression

Abstract

The paraventricular nucleus of the hypothalamus (PVH) plays a central role in regulating the hypothalamic-pituitary-adrenal (HPA) axis. Medial parvocellular neurons of the PVH (mpPVH) integrate sensory and humoral inputs to maintain homeostasis. Humeral inputs include glucocorticoids secreted by the adrenals, which down-regulate HPA activation. A primary glucocorticoid target is the population of mpPVH neurons that synthesize and secrete corticotropin-releasing factors, the most potent of which is corticotropin-releasing hormone (CRH). Although CRH gene (crh) expression is known to be down-regulated by glucocorticoids, the mechanisms by which this process occurs are still poorly understood. To begin this study we postulated that glucocorticoid repression of crh involves HDAC recruitment to the region of the crh proximal promoter. To evaluate this hypothesis, we treated hypothalamic cells that express CRH with the HDAC inhibitor trichostatin A (TSA). As predicted, treatment with TSA led to increased CRH mRNA levels and crh promoter activity. Although co-treatment with Dex (10−7 M) reduced the TSA effect on mRNA levels, it failed to reduce promoter activity; however co-transfection of HDAC1 but not 3 restored Dex inhibition. A distinction between HDAC1 and 3 was also apparent with respect to crh promoter occupancy. Dex led to increased HDAC1 but not HDAC3 occupancy. In vivo studies revealed that CRH-immunoreactive (-ir) neurons contained HDAC1- and HDAC3-ir. Collectively, these data point to a role for HDAC1 in the physiologic regulation of crh.

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

“…Epigenetic regulation of gene expression via DNA/histone modifications is known to control aspects of hypothalamic function, such as hormone synthesis (Miller et al, 2011) and sexual maturation of the brain (Matsuda et al, 2011). In some cases, this is believed to be a behavioural control mechanism that, for instance, contributes to imprinting action of the environment on the young animal that results in altered behaviour in the mature animal.…”

“…In the hypothalamus, HDACs are involved in masculinization of the brain during the early postnatal period potentially through the nuclear receptor estrogen receptor α and aromatase (Matsuda et al, 2011). Control of corticotropin‐releasing hormone in the hypothalamus by the glucocorticoid receptor, another member of the nuclear receptor superfamily, is potentially mediated by HDACI (Miller et al, 2011). Epigenetic changes in the DNA methylation and histone acetylation states of the promoters of hypothalamic genes involved in energy balance, such as Pomc and Npy , have been found to result from maternal undernutrition or stress (Paternain et al, 2012; Stevens et al, 2010).…”

Mechanisms of Glucocorticoid Receptor (GR) Mediated Corticotropin Releasing Hormone Gene Expression

“…As is the case in estradiol regulation, Dex regulates H3 and H4 acetylation differentially, as measured by chromatin immunoprecipitation followed by PCR amplification (Miller et al 2011). Dex increases H4 acetylation, a finding that underscores the fact that acetylation may be associated a state of repression as well as activation.…”

“…Given the conserved nature of many functions across nuclear receptors one might predict that like the TR, GR-repressed transcription of crh expression would involve HDAC3 but not HDAC1. In the context of the crh promoter, however, the reverse is true (Miller et al 2011).…”

“…Like Sir2, they are targets of intense study given their association with aging and neurodegenerative processes. Because HDACs are tightly correlated with repression they have been examined in the context of GR-repressed crh expression (Miller et al 2011).…”