A seasonal switch in histone deacetylase gene expression in the hypothalamus and their capacity to modulate nuclear signaling pathways

Patrick N Stoney,Diana Rodrigues,Gisela Helfer,Thabat Khatib,Anna Ashton,Elizabeth A Hay,Robert Starr,Dagmara Kociszewska,Peter Morgan,Peter Mccaffery

doi:10.1016/j.bbi.2016.12.013

Patrick N Stoney, Diana Rodrigues + Show 8 more

Open Access

https://doi.org/10.1016/j.bbi.2016.12.013

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Abstract

Seasonal animals undergo changes in physiology and behavior between summer and winter conditions. These changes are in part driven by a switch in a series of hypothalamic genes under transcriptional control by hormones and, of recent interest, inflammatory factors. Crucial to the control of transcription are histone deacetylases (HDACs), generally acting to repress transcription by local histone modification. Seasonal changes in hypothalamic HDAC transcripts were investigated in photoperiod-sensitive F344 rats by altering the day-length (photoperiod). HDAC4, 6 and 9 were found to change in expression. The potential influence of HDACs on two hypothalamic signaling pathways that regulate transcription, inflammatory and nuclear receptor signaling, was investigated. For inflammatory signaling the focus was on NF-κB because of the novel finding made that its expression is seasonally regulated in the rat hypothalamus. For nuclear receptor signaling it was discovered that expression of retinoic acid receptor beta was regulated seasonally. HDAC modulation of NF-κB-induced pathways was examined in a hypothalamic neuronal cell line and primary hypothalamic tanycytes. HDAC4/5/6 inhibition altered the control of gene expression (Fos, Prkca, Prkcd and Ptp1b) by inducers of NF-κB that activate inflammation. These inhibitors also modified the action of nuclear receptor ligands thyroid hormone and retinoic acid. Thus seasonal changes in HDAC4 and 6 have the potential to epigenetically modify multiple gene regulatory pathways in the hypothalamus that could act to limit inflammatory pathways in the hypothalamus during long-day summer-like conditions.

Highlights

This study focused on possible epigenetic changes that may be part of this seasonal switch, examining alterations in gene expression of histone deacetylase (HDAC), which deacetylate histones, promoting chromatin condensation and suppressing gene expression
For Hdac4, these changes in mRNA expression were evident in the ependymal cells and tanycytes lining the third ventricle and when measured in these cells, the change in gene expression was large (5-fold)
thyroid-stimulating hormone (TSH) was shown to induce Hdac4 expression both in vivo and ex vivo and TSH is likely to act as an intermediary by which melatonin may trigger seasonal changes in Hdac4 expression, as is the case for a number of other genes which are key intermediaries in melatonin’s control of seasonal change in the hypothalamus (Dardente et al, 2014)

Summary

Introduction

There is a growing interest in the regulation of hypothalamic function by epigenetic mechanisms – control of gene expression via chemical modifications of DNA or chromatin (Gali Ramamoorthy et al, 2015). Histone deacetylases (HDACs) are essential mediators of epigenetic regulation and act by removing acetyl groups from lysine residues of histones, leading to chromatin condensation and transcriptional repression. The HDACs fall into four groups, primarily based on homology to yeast equivalent genes: class I (HDACs1, 2, 3 and 8), class IIa (HDACs 4, 5, 7 and 9), class IIb (HDACs 6 and 10), and class IV, consisting of HDAC11 alone.

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