Cyto-nuclear shuttling of afadin is required for rapid estradiol-mediated modifications of histone H3

Abstract

Estrogens have been shown to rapidly regulate local signalling events at both synapses and within the nucleus. The result of these signalling events is to rapidly modulate synapse structure and function, as well as epigenetic mechanisms including histone modifications.Ultimately these mechanisms are thought to contribute to long-lasting changes in neural circuitry, and thus influences cognitive functions such as learning and memory. However, the mechanisms by which estrogen-mediated local synaptic and nuclear signalling events are coordinated are not well understood. In this study we have found that the scaffold protein afadin, (also known as AF-6), undergoes a bi-directional trafficking to both synaptic and nuclear compartment in response to acute 17β-estradiol (estradiol) treatment. Interestingly, nuclear accumulation of afadin was coincidental with an increase in the phosphorylation of histone H3 at serine 10 (H3S10p). This histone modification is associated with the remodelling of chromatin into an open euchromatin state, allowing for transcriptional activation and related learning and memory processes. Critically, the cyto-nuclear trafficking of afadin was required for estradiol-dependent H3S10p. We further determined that nuclear accumulation of afadin is sufficient to induce phosphorylation of the mitogentic kinases ERK1/2 (pERK1/2) within the nucleus. Moreover, nuclear pERK1/2 was required for estradiol-dependent H3S10p. Taken together, we propose a model whereby estradiol incudes the bi-directional trafficking of afadin to synaptic and nuclear sub-compartments. Within the nucleus, afadin is required for increased pERK1/2 which in turn is required for H3S10p. Therefore this represents a mechanism through which estrogens may be able to coordinate both synaptic and nucleosomal events within the same neuronal population.

Extracellular histone H3 facilitates ferroptosis in sepsis through ROS/JNK pathway

“…Moreover, E2 was able to reverse such an accelerating function. There is evidence that E2 is involved in the regulation of histone H3 acetylation and phosphorylation 43,44 . We speculate that E2 is also involved in the regulation of extracellular histone expression, thereby achieving its therapeutic effect in sepsis.…”

“…There is evidence that E2 is involved in the regulation of histone H3 acetylation and phosphorylation. 43,44 We speculate that E2 is also involved in the regulation of extracellular histone expression, thereby achieving its therapeutic effect in sepsis. Due to the limitations of the research conditions, we were unable to further explore the relationship between E2 and histone in this study, which may be studied in the future.…”

AFDN (afadin, adherens junction formation factor)

“…Accumulation of afadin in the nucleus induces phosphorylation of kinases MAPK3 / MAPK1 (pERK1/2), phosphorylation of RPS6KA1 (p90RSK) that can directly phosphorylate histone H3 at serine 10 (H3S10p.). This in turn contributes to long term alterations in synapse structure (VanLeeuwen et al, 2014;Sellers et al, 2018).…”