Extreme weather events frequency and scale are altered due to climate change. Symbiosis between corals and their endosymbiotic-dinoflagellates (Symbiodinium) is susceptible to these events and can lead to what is known as bleaching. However, there is evidence for coral adaptive plasticity in the role of epigenetic that have acclimated to high-temperature environments. We have implemented ATAC-seq and RNA-seq to study the cnidarian-dinoflagellate model Exaptasia pallida (Aiptasia) and expose the role of chromatin-dynamics in response to thermal-stress. We have identified 1309 genomic sites that change their accessibility in response to thermal changes. Moreover, apo-symbiotic Aiptasia accessible sites were enriched with NFAT, ATF4, GATA3, SOX14, and PAX3 motifs and expressed genes related to immunological pathways. Symbiotic Aiptasia accessible sites were enriched with NKx3-1, HNF4A, IRF4 motifs and expressed genes related to oxidative-stress pathways. Our work opens a new path towards understanding thermal-stress gene regulation in association with gene activity and chromatin-dynamics.

In animals, circadian rhythms are driven by oscillations in transcription, translation, and proteasomal degradation of highly conserved genes, resulting in diel cycles in the expression of numerous clock-regulated genes. Transcription is largely regulated through the binding of transcription factors to cis-regulatory elements within accessible regions of the chromatin. Chromatin remodeling is linked to circadian regulation in mammals, but it is unknown whether cycles in chromatin accessibility are a general feature of clock-regulated genes throughout evolution. To assess this, we applied an ATAC-seq approach using Nematostella vectensis, grown under two separate light regimes (light:dark (LD) and constant darkness (DD)). Based on previously identified N. vectensis circadian genes, our results show the coupling of chromatin accessibility and circadian transcription rhythmicity under LD conditions. Out of 180 known circadian genes, we were able to list 139 gene promoters that were highly accessible compared to common promoters. Furthermore, under LD conditions, we identified 259 active enhancers as opposed to 333 active enhancers under DD conditions, with 171 enhancers shared between the two treatments. The development of a highly reproducible ATAC-seq protocol integrated with published RNA-seq and ChIP-seq databases revealed the enrichment of transcription factor binding sites (such as C/EBP, homeobox, and MYB), which have not been previously associated with circadian signaling in cnidarians. These results provide new insight into the regulation of cnidarian circadian machinery. Broadly speaking, this supports the notion that the association between chromatin remodeling and circadian regulation arose early in animal evolution as reflected in this non-bilaterian lineage. The phenotype of an organism cannot be fully explained by its genome; it is now clear that other factors contribute to the ecology and evolution of animals. The DNA molecule is exceptionally long and has to fit into a small nucleus; therefore, the DNA is wound around proteins called histones in a unique architectural complex called a nucleosome (that further forms the chromatin). This DNA structure plays a crucial role in gene regulation, as nucleosomes alternate accessibility to regulatory sites, that in turn navigate expression patterns that allow gene expression or suppression. It is well known that chromatin remodeling is associated with circadian regulation in mammals, but it was uncertain whether cycles in chromatin accessibility are a conserved feature of clock-regulated genes throughout the animal kingdom. We used ATAC-seq and RNA-seq data to show that the association between chromatin remodeling and circadian regulation arose early in animal evolution as reflected in the sea anemone, Nematostella vectensis, model organism.

The profound mutualistic symbiosis between corals and their endosymbiotic counterparts, Symbiodiniaceae algae, has been threatened by the increase in seawater temperatures, leading to breakdown of the symbiotic relationship—coral bleaching. To characterize the heat-stress response of the holobiont, we generated vital apo-symbiotic Euphyllia paradivisa corals that lacked the endosymbiotic algae. Using RNA sequencing, we analyzed the gene expression of these apo-symbionts vs. symbiotic ones, to test the effect of the algal presence on the tolerance of the coral. We utilized literature-derived lists of “symbiosis differentially expressed genes” and “coral heat-stress genes” in order to compare between the treatments. The symbiotic and apo-symbiotic samples were segregated into two separate groups with several different enriched gene ontologies. Our findings suggest that the presence of endosymbionts has a greater negative impact on the host than the environmental temperature conditions experienced by the holobiont. The peak of the stress reaction was identified as 28 °C, with the highest number of differentially expressed genes. We suggest that the algal symbionts increase coral holobiont susceptibility to elevated temperatures. Currently, we can only speculate whether coral species, such as E. paradivisa, with the plasticity to also flourish as apo-symbionts, may have a greater chance to withstand the upcoming global climate change challenge.

Organisms’ survival is associated with the ability to respond to natural or anthropogenic environmental stressors. Frequently, these responses involve changes in gene regulation and expression, consequently altering physiology, development, or behavior. Here, we present modifications in response to heat exposure that mimics extreme summertime field conditions of lab-cultured and field-conditioned Nematostella vectensis. Using ATAC-seq and RNA-seq data, we found that field-conditioned animals had a more concentrated reaction to short-term thermal stress, expressed as enrichment of the DNA repair mechanism pathway. By contrast, lab animals had a more diffuse reaction that involved a larger number of differentially expressed genes and enriched pathways, including amino acid metabolism. Our results demonstrate that pre-conditioning affects the ability to respond efficiently to heat exposure in terms of both chromatin accessibility and gene expression and reinforces the importance of experimentally addressing ecological questions in the field.

Loss of nuclear TDP-43 splicing activity is a common feature across neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but its relevance to Alzheimer's disease (AD) remains unclear. Here, we show that TDP-43 pathology in AD is broadly associated with splicing abnormalities, including aberrant splicing of amyloid precursor protein (APP). TDP-43 drives the formation of elongated APP isoforms, disrupting alternative splicing across ALS, FTLD-TDP and AD, providing a compelling mechanism for a long-standing observation of APP isoform dysregulation. We further establish a mechanistic link between TDP-43, APP splicing, and A-beta pathology. Surprisingly, the disruption to alternative APP splicing is mediated by a toxic gain of cytoplasmic TDP-43 function, rather than loss of its nuclear role. Using proximity proteomics and base editing in human iPSC-derived neurons, we show that TDP-43 pathology causes cytoplasmic co-sequestration of splicing regulators SCAF11, SRSF5, and TIAL1. Knockdown of these regulators also results in APP mis-splicing and increased A-beta burden, without affecting other TDP-43 targets such as STMN2 or UNC13A. Together, our findings suggest that TDP-43-mediated splicing dysfunction upstream of APP contributes to the pathogenesis of seemingly disparate neurodegenerative diseases, uniting AD and ALS/FTLD-TDP through a shared molecular mechanism.

Background: Estrogen receptor alpha (ERα)-positive luminal breast cancer is commonly treated with aromatase inhibitors (AI) to block estrogen signaling; however, resistance frequently develops, limiting therapy success. Results: We observed that GLYATL1 (Glycine-N-Acyltransferase Like 1) expression is upregulated in AI-resistant breast cancer cell models and in patients undergoing AI therapy, correlating with poorer survival. Here we demonstrate that GLYATL1 promotes resistance to estrogen deprivation by elevating succinate levels and altering epigenetic histone marks associated with active transcription. Knockdown or knockout of GLYATL1 reverses these effects and reduces proliferation under estrogen-deprived conditions. Notably, GLYATL1 expression is positively regulated by estrogen receptor alpha signaling, however, independently of estrogen. Conclusions: These findings reveal GLYATL1 as a metabolic and epigenetic mediator of endocrine therapy resistance, suggesting it as a potential target to overcome AI resistance in luminal breast cancer.