Kdm6b and Pmepa1 as Targets of Bioelectrically and Behaviorally Induced Activin A Signaling

Abstract

The transforming growth factor-β (TGF-β) family member activin A exerts multiple neurotrophic and protective effects in the brain. Activin also modulates cognitive functions and affective behavior and is a presumed target of antidepressant therapy. Despite its important role in the injured and intact brain, the mechanisms underlying activin effects in the CNS are still largely unknown. Our goal was to identify the first target genes of activin signaling in the hippocampus in vivo. Electroconvulsive seizures, a rodent model of electroconvulsive therapy in humans, were applied to C57BL/6J mice to elicit a strong increase in activin A signaling. Chromatin immunoprecipitation experiments with hippocampal lysates subsequently revealed that binding of SMAD2/3, the intracellular effectors of activin signaling, was significantly enriched at the Pmepa1 gene, which encodes a negative feedback regulator of TGF-β signaling in cancer cells, and at the Kdm6b gene, which encodes an epigenetic regulator promoting transcriptional plasticity. Underlining the significance of these findings, activin treatment also induced PMEPA1 and KDM6B expression in human forebrain neurons generated from embryonic stem cells suggesting interspecies conservation of activin effects in mammalian neurons. Importantly, physiological stimuli such as provided by environmental enrichment proved already sufficient to engender a rapid and significant induction of activin signaling concomitant with an upregulation of Pmepa1 and Kdm6b expression. Taken together, our study identified the first target genes of activin signaling in the brain. With the induction of Kdm6b expression, activin is likely to gain impact on a presumed epigenetic regulator of activity-dependent neuronal plasticity.

Acute and Chronic Electroconvulsive Seizures (ECS) Differentially Regulate the Expression of Epigenetic Machinery in the Adult Rat Hippocampus

“…In our profiling of the regulation of KDMs that catalyze the removal of histone methylation marks, we noted a robust induction of Jmjd3 hippocampal expression following both acute (2.8-fold) and chronic (2.4-fold) ECS. Our results are in agreement with a previous report that indicates a significant induction of Jmjd3 in the hippocampus 2 hours following acute ECS ( Link et al, 2015 ). JMJD3 catalyzes the removal of methyl groups from H3K27me3, a repressive epigenetic mark, and has been shown to play a vital role in the regulation of adult neurogenesis, through the regulation of key neurogenic genes via interactions within both promoter and enhancer elements ( Park et al, 2014a ).…”

“…However, only a few reports have directly examined whether ECS or neuronal activity can influence the expression of epigenetic enzymatic machinery itself. ECS treatment can perturb the expression of Hdac2 ( Park et al, 2014b ), Sirt1 ( Chung et al, 2013 ), Jmjd3 ( Link et al, 2015 ), Gadd45b ( Ma et al, 2009 ; Jun et al, 2015 ), and Dnmt1 and Dnmt3a ( Dyrvig et al, 2015 ) and is associated with alterations in the global methylation profile, primarily within the hippocampus ( Guo et al, 2011a ). Further, neuronal activity regulates the gene expression of the Ten-eleven translocation (TET) proteins, Tet1 and Tet3 , which catalyze the conversion of 5-methylcytosine to 5-hydroxymethylcytosine ( Kaas et al, 2013 ; Yu et al, 2015 ).…”

H3.3 Barcoding of Nucleus Accumbens Transcriptional Activity Identifies Novel Molecular Cascades Associated with Cocaine Self-administration in Mice

“…The other novel target identified in this study, Pmepa1, a member of the TGF-␤ family, modulates cell proliferation and differentiation as well as immune responses, and is thus often studied in the context of cancer (Itoh and Itoh, 2018). In the brain, Pmepa1 expression is increased by activin A, another TGF-␤ family member, and inhibits activin A signaling by decreasing phosphorylation of SMAD2/3 in a negative feedback loop (Link et al, 2016). To our knowledge, no studies have explored Pmepa1 in response to cocaine; however, activin signaling via SMAD3 is increased following withdrawal from cocaine selfadministration, and SMAD3 mediates cocaine-induced plasticity in dendritic spines in the NAcc (Gancarz et al, 2015).…”

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

“…Hence, their downregulation reasonably impacts brain bioenergetics in SZ and also in other disorders featuring co gnitive impairment [Rosa and César, 2016]. Interestingly, KDM6B , a target of activin signaling involved in cognitive function and affective behavior [Link et al, 2016], is also upregulated in the SZ hippocampus ( Fig. 4 a).…”