Abstract
The immediate early genes (IEGs) c-Fos and Egr-1 are rapidly and transiently induced in sparse neurons within the hippocampus after exposure to an acute stressor. The induction of these genes is a critical part of the molecular mechanisms underlying successful behavioral adaptation to stress. Our previous work has shown that transcriptional activation of c-Fos and Egr-1 in the hippocampus requires formation of a dual histone mark within their promoter regions, the phosphorylation of serine 10 and acetylation of lysine 9/14 of histone H3. In the present study, using chromatin immuno-precipitation (ChIP), we found that an increase in the formation of H3K9ac-S10p occurs within the c-Fos and Egr-1 promoters after FS stress in vivo and that these histone modifications were located to promoter regions containing cAMP Responsive Elements (CREs), but not in neighboring regions containing only Serum Responsive Elements (SREs). Surprisingly, however, subsequent ChIP analyses showed no changes in the binding of pCREB or CREB-binding protein (CBP) to the CREs after FS. In fact, pCREB binding to the c-Fos and Egr-1 promoters was already highly enriched under baseline conditions and did not increase further after stress. We suggest that constitutive pCREB binding may keep c-Fos and Egr-1 in a poised state for activation. Possibly, the formation of H3K9ac-S10p in the vicinity of CRE sites may participate in unblocking transcriptional elongation through recruitment of additional epigenetic factors.
Highlights
Immediate early genes (IEGs) such as FBJ osteosarcoma oncogene (c-Fos) and Early growth response 1 (Egr-1) are induced rapidly in response to a challenge
We found that FC led to significant, transient increases in cFos and Egr-1 mRNA in all hippocampal sub-regions studied (Figure 1)
Induction of these genes is under very stringent control involving multiple signaling and epigenetic mechanisms (Gutierrez-Mecinas et al, 2011; Papadopoulos pCREB Binding in the Hippocampus et al, 2011; Carter et al, 2015; Saunderson et al, 2016)
Summary
Immediate early genes (IEGs) such as FBJ osteosarcoma oncogene (c-Fos) and Early growth response 1 (Egr-1) are induced rapidly in response to a challenge This rapid response is the result of a complex cascade of molecular events including intracellular signaling, chromatin modifications and transcription factor binding in the promoter regions of the genes (Gutierrez-Mecinas et al, 2011; O’Donnell et al, 2012; Reul, 2014). Within the c-Fos and Egr-1 promoter regions, CREB binds to cAMP responsive elements (CREs) whereas a complex of serum response factor (SRF) and pElk-1 (phosphorylated ETS domain-containing protein) binds to serum response elements (SREs) (Changelian et al, 1989; Defranco et al, 1993; Robertson et al, 1995). CREB, and in particular CREB-dependent gene transcription, is thought to be vital for long-term memory (Bourtchuladze et al, 1994)
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