Abstract
Successful attenuation of fearful memories is a cognitive process requiring initiation of highly coordinated transcription programs. Chromatin-modulating mechanisms such as DNA methylation and histone modifications, including acetylation, are key regulators of these processes. However, knowledge concerning the role of ATP-dependent chromatin remodeling factors (ChRFs) being required for successful fear extinction is lacking. Underscoring the potential importance of these factors that alter histone-DNA contacts within nucleosomes are recent genome-wide association studies linking several ChRFs to various human cognitive and psychiatric disorders. To better understand the role of ChRFs in the brain, and since to date little is known about ChRF expression in the brain, we performed a comprehensive survey of expression levels of 24 ATP-dependent remodelers across different brain areas, and we identified several distinct high molecular weight complexes by chromatographic methods. We next aimed to gain novel insight into the potential regulation of ChRFs in different brain regions in association with normal and impaired fear extinction learning. To this end, we established the 129S1/SvImJ (S1) laboratory mouse strain as a model for compromised contextual fear extinction learning that can be rescued by dietary zinc restriction (ZnR). Using this model along with genetically related but fear extinction-competent 129S6/SvEv (S6) mice as controls, we found that impaired fear extinction in S1 was associated with enhanced ventral hippocampal expression of CHD1 and reduced expression of CHD5 that was normalized following successful rescue of impaired fear extinction. Moreover, a select reduction in CHD3 expression was observed in the ventral hippocampus (vHC) following successful rescue of fear extinction in S1 mice. Taken together, these data provide novel insight into the regulation of specific ChRFs following an impaired cognitive process and its rescue, and they suggest that imbalance of CHD-type remodeler levels, which consequently may lead to changes of transcriptional programs, may be an underlying mechanism involved in impaired fear extinction learning and its therapeutic rescue.
Highlights
Anxiety and trauma-related disorders are the most prevalent mental disorders in Western societies, with current estimates suggesting that 30% of the population may be afflicted at least once during their lifetime (Kessler et al, 2005; Wittchen et al, 2011)
Some factors display specific expression patterns within the brain: for instance, CHD7 is overrepresented in the cerebellum, while CHD5 is depleted from the cerebellum but slightly enriched in the hypothalamus and the cortex; CHD6 is relatively depleted in the hippocampus/thalamus/septum region and BTAF1 is relatively enriched in the olfactory bulb (Figure 1B)
We focused on factors of the CHD-subfamily of chromatin remodeling factors (ChRFs) (CHD1, CHD3, CHD5) and on ATRX for the following reasons: (i) Antibodies against these factors were commercially available and successfully detected the corresponding proteins in brain protein extracts (Note: we tested antibodies against CHD2, CHD4, and CHD7 but obtained either no or very faint signals or signals that did not correspond to the calculated size of the protein). (ii) CHD3 and 5 show relatively high expression on the transcript level enabling detection with limited tissue amount. (iii) All these factors have been linked to brain development and/or brain function before (Gaspar-Maia et al, 2009; Bérubé, 2011; Nogami et al, 2011; Potts et al, 2011; Piatti et al, 2015)
Summary
Anxiety and trauma-related disorders are the most prevalent mental disorders in Western societies, with current estimates suggesting that 30% of the population may be afflicted at least once during their lifetime (Kessler et al, 2005; Wittchen et al, 2011) These disorders including phobias, panic, and posttraumatic stress disorder have an important learning component and are often associated with impaired extinction learning, the central mechanism for successful exposure-based therapies (Bouton et al, 2001; Mineka and Zinbarg, 2006). ChRFs use the energy derived from ATP hydrolysis to disrupt and reform histone-DNA contacts. This activity can result in diverse outcomes ranging from the repositioning of nucleosomes along the DNA (sliding), to ejection and assembly of nucleosomes or replacement of canonical with variant histones (Clapier and Cairns, 2009). Access to the DNA for transcription factors and the transcription machinery is enhanced or suppressed leading to activation or repression of gene activity
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