Nuclear Gene Transcription Research Articles

SlPGR5/SlPGRL1 pathway-dependent cyclic electron transport regulates photoprotection and chloroplast quality in tomato plants

The essential photoprotective role of proton gradient regulation 5 (PGR5)-dependent cyclic electron flow (CEF) has been reported in Arabidopsis, rice, and algae. However, its functional assessment has not been performed in tomato yet. In this study, we focused on elucidate the function of SlPGR5 and SlPGR5-like photosynthetic phenotype 1 (PGRL1) in tomato. We performed RNA interference and found that SlPGR5/SlPGRL1-suppressed transformants exhibited extremely low CO2 assimilation capacity, their photosystem I (PSI) and PSII were severely photoinhibited and chloroplasts were obviously damaged. The SlPGR5/SlPGRL1-suppressed plants almost completely inhibited CEF and Y(ND), and PSII photoinhibition may be directly related to the inability to produce sufficient proton motive force to induce NPQ. The transgenic plants overexpressing SlPGR5 and SlPGRL1 driven by 35S promoter capable alleviate photoinhibition of plants under low night temperature. The transcriptomic and proteomic analyses suggested that the nuclear gene transcription and turnover of chloroplast proteins, including the plastoglobule-related proteins, were closely related to SlPGR5/SlPGRL1 pathway dependent CEF. The bridge relationship between CEF and chloroplast quality maintenance was a novel report to our knowledge. In conclusion, these results revealed the regulatory mechanism of the SlPGR5/SlPGRL1 pathway in photoprotection and maintenance of chloroplast function in tomato, which is crucial for reduce yield loss, especially under adverse environmental conditions.

Deletion of MOF in CD4 T cells results in mitochondrial dysfunction, Th17 polarization, and colonic inflammation.

Abstract Introduction: The enzyme, MOF (males absent of the first), is a histone acetyltransferase that regulates the transcription of nuclear and mitochondrial genes. The role of MOF in acquired immunity has not been established. Hypothesis: Expression of MOF controls CD4 T cell phenotype by regulating cellular metabolism. Materials, Methods, and Results: We generated mice selectively deficient in MOF in CD4 T cells (Moff/f CD4cre). After ex vivo stimulation with CD3 and CD28, MOF-deficient splenic CD4 T cells displayed lower proliferation rate and viability, associated with altered mitochondrial morphology by electron microscopy, impaired oxidative phosphorylation, and higher glycolytic capacity, lactate production, and higher ATP production. In vivo, Moff/f CD4cre mice developed spontaneous rectal prolapse and colonic cryptitis. Intraepithelial and lamina propria CD4 T cell from these animals were disproportionately activated and displayed a Th17 phenotype. Treating these animals with a mitochondrion-targeted antioxidant, mitotempo, for a month resulted in normalization of T cell ATP production and lactate production. Conclusion: The histone acetyltransferase MOF moderates T cell activation and polarization by controlling mitochondrial respiration, protecting against the spontaneous development of colitis.

Redox regulation of gene expression: proteomics reveals multiple previously undescribed redox-sensitive cysteines in transcription complexes and chromatin modifiers.

Redox signalling is crucial for regulating plant development and adaptation to environmental changes. Proteins with redox-sensitive cysteines can sense oxidative stress and modulate their functions. Recent proteomics efforts have comprehensively mapped the proteins targeted by oxidative modifications. The nucleus, the epicentre of transcriptional reprogramming, contains a large number of proteins that control gene expression. Specific redox-sensitive transcription factors have long been recognized as key players in decoding redox signals in the nucleus and thus in regulating transcriptional responses. Consequently, the redox regulation of the nuclear transcription machinery and its cofactors has received less attention. In this review, we screened proteomic datasets for redox-sensitive cysteines on proteins of the core transcription complexes and chromatin modifiers in Arabidopsis thaliana. Our analysis indicates that redox regulation affects every step of gene transcription, from initiation to elongation and termination. We report previously undescribed redox-sensitive subunits in transcription complexes and discuss the emerging challenges in unravelling the landscape of redox-regulated processes involved in nuclear gene transcription.

AβPP-tau-HAS1 axis trigger HAS1-related nuclear speckles and gene transcription in Alzheimer's disease

As the backbone of the extracellular matrix (ECM) and the perineuronal nets (PNNs), hyaluronic acid (HA) provides binding sites for proteoglycans and other ECM components. Although the pivotal of HA has been recognized in Alzheimer's disease (AD), few studies have addressed the relationship between AD pathology and HA synthases (HASs). Here, HASs in different regions of AD brains were screened in transcriptomic database and validated in AβPP/PS1 mice. We found that HAS1 was distributed along the axon and nucleus. Its transcripts were reduced in AD patients and AβPP/PS1 mice. Phosphorylated tau (p-tau) mediates AβPP-induced cytosolic-nuclear translocation of HAS1, and negatively regulated the stability, monoubiquitination, and oligomerization of HAS1, thus reduced the synthesis and release of HA. Furthermore, non-ubiquitinated HAS1 mutant lost its enzyme activity, and translocated from the cytosol into the nucleus, forming nuclear speckles (NS). Unlike the splicing-related NS, less than 1 % of the non-ubiquitinated HAS1 co-localized with SRRM2, proving the regulatory role of HAS1 in gene transcription, indirectly. Thus, differentially expressed genes (DEGs) related to both non-ubiquitinated HAS1 mutant and AD were screened using transcriptomic datasets. Thirty-nine DEGs were identified, with 64.1 % (25/39) showing consistent results in both datasets. Together, we unearthed an important function of the AβPP-p-tau-HAS1 axis in microenvironment remodeling and gene transcription during AD progression, involving the ubiquitin-proteasome, lysosome, and NS systems.

Excitation-transcription coupling, neuronal gene expression and synaptic plasticity.

Excitation-transcription coupling (E-TC) links synaptic and cellular activity to nuclear gene transcription. It is generally accepted that E-TC makes a crucial contribution to learning and memory through its role in underpinning long-lasting synaptic enhancement in late-phase long-term potentiation and has more recently been linked to late-phase long-term depression: both processes require de novo gene transcription, mRNA translation and protein synthesis. E-TC begins with the activation of glutamate-gated N-methyl-D-aspartate-type receptors and voltage-gated L-type Ca2+ channels at the membrane and culminates in the activation of transcription factors in the nucleus. These receptors and ion channels mediate E-TC through mechanisms that include long-range signalling from the synapse to the nucleus and local interactions within dendritic spines, among other possibilities. Growing experimental evidence links these E-TC mechanisms to late-phase long-term potentiation and learning and memory. These advances in our understanding of the molecular mechanisms of E-TC mean that future efforts can focus on understanding its mesoscale functions and how it regulates neuronal network activity and behaviour in physiological and pathological conditions.

Pathological classification of malignant peritoneal mesothelioma and comparative analysis with peritoneal carcinomatosis

Objective: To analyze the pathological classification of malignant peritoneal mesothelioma (MPeM) and screen the immunohistochemical markers that can distinguish MPeM from peritoneal metastatic carcinoma (PC) . Methods: In June 2020, the pathological results of peritoneal biopsy of 158 MPeM and 138 PC patients from Cangzhou Central Hospital, Cangzhou People's Hospital, and Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine from May 2011 to July 2019 were retrospectively analyzed, and the pathological classifications of MPeM in Cangzhou were summarized. Immunohistochemical markers of MPeM and PC patients were analyzed, and receiver operating characteristic curve (ROC curve) was drawn for differential diagnosis of MPeM and PC. Results: There were 55 male and 103 female MPeM patients in Cangzhou, with an average age of 57.1 years old. The asbestos exposure rate was 91.14% (144/158). The most common pathological classifications were cutaneous type, accounting for 90.51% (143/158). There were significant differences in the expression of calreticulum protein, CK5/6, vimentin, D2-40, carcinoembryonic antigen (CEA) and tail type homologous nuclear gene transcription factor 2 (CDX-2) between MPeM and PC (P<0.05). Among the 6 positive markers, the sensitivity of calreticulum protein was the highest (0.905) and CEA was the lowest (0.428) . Conclusion: Calreticulum protein, CK5/6, vimentin, D2-40, CEA and CDX-2 may be used as specific markers to distinguish the diagnosis of MPeM from PC.

Slimming and Reinvigorating Tumor-Associated Dendritic Cells with Hierarchical Lipid Rewiring Nanoparticles.

Dendritic cells (DCs) are crucial mediators of innate and adaptive antitumor immunity, whereas exogenously and endogenously driven lipid accumulation causes immune tolerance of tumor-associated DCs (TADCs) and thereby diminishes tumor responsiveness to various therapies. Herein, a type of multilevel lipid rewiring nanoparticles (NPs) for TADC revitalization is designed. These self-assembled NPs specifically bind to the lipid transport receptor Msr1 on the TADC surface and orchestrate the restriction of extracellular lipid uptake, cytoplasmic de novo lipid biosynthesis and nuclear lipogenic gene transcription. It is found that the slimming of TADCs via the three-in-one lipid metabolic reprogramming substantially promotes their maturation and rehabilitate their functions in inflammatory cytokine production, cytotoxic T cell recruitment, and tumor inhibition. Significantly, tumor resistance to immune checkpoint blockade therapy is further overcome. The study presents a non-canonical strategy to remodel tumor-infiltrating immune cells and paves a new path for improving the efficacy of cancer immunotherapy.

Targeting the YAP/TAZ mechanotransducers in solid tumour therapeutics.

Targeting the YAP/TAZ mechanotransducers in solid tumour therapeutics.

Impact of waterpipe and tobacco cigarette smoking on global DNA methylation and nuclear proteins genes transcription in spermatozoa: a comparative investigation

Background Waterpipe smoking is harmful and dangerous, and it is a growing threat to public health. Objectives This study was performed to evaluate the influence of waterpipe smoking on global DNA methylation, DNA fragmentation, and protamine deficiency in spermatozoa compared to cigarette heavy smokers and nonsmokers, and to determine whether the transcription levels of spermatozoa nuclear proteins genes ‘PRM1, PRM2, and H2BFWT’ in waterpipe smokers are different compared to cigarette heavy smokers and nonsmokers. Methods A total of 900 semen samples were collected from males with a mean age of 32.5 ± 6.3 years (300 waterpipe smokers, 300 cigarette heavy smokers, and 300 nonsmokers). The nucleic acids were isolated from purified spermatozoa, and then the global DNA methylation and transcription levels of the PRM1, PRM2, and H2BFWT genes were assessed using ELISA and qPCR, respectively. Results A significant increase was found in the level of global DNA methylation (8.6 ± 0.6 ng/μl vs. 7.1 ± 0.6 ng/μl and 4.7 ± 0.6 ng/μl, p < 0.001), protamine deficiency (72.8 ± 15.3 vs. 51.7 ± 19.2 and 15.3 ± 5.9%, p < 0.001), and DNA fragmentation (73.4 ± 13.4 vs. 50.5 ± 18.9 and 9.3 ± 4.3%, p < 0.001) in waterpipe smokers compared to cigarette heavy smokers and nonsmokers. A significant increase was shown in the transcription levels of PRM1, PRM2, and H2BFWT genes in waterpipe smokers compared to cigarette heavy smokers and nonsmokers (p < 0.001). A down-regulation was found in the transcription level of these genes in different smoker groups compared to nonsmokers (<0.001). Conclusion This study suggests that waterpipe smoking is more harmful than cigarette smoking on semen parameters, global DNA methylation, and transcription of nuclear protein genes.

Abstract 1614: Antitumor activity of novel and potent YAP/TAZ-TEAD inhibitorstargeting the Hippo pathway in solid tumors

Abstract The Hippo pathway is evolutionarily conserved and known to regulate diverse cellular processes, including cell survival, proliferation, differentiation, migration, and organ size. The key regulator of Hippo pathway is transcriptional enhanced associate domain (TEAD) transcription factors, which directly bind with YAP/TAZ and then drive the multiple signaling by activating target gene expression on nuclear. Loss-of-function mutations in the upstream activators, NF2-LATS1/2-MST1/2, trigger YAP/TAZ nuclear translocation and target gene transcription (Hippo-off state). This YAP/TAZ-TEAD complex is overexpressed and leads to metastatic progression in various cancers including malignant mesothelioma, NSCLC, ovarian cancer or cholangiocarcinoma. A recent development in targeting the Hippo pathway has been focused on the discovery of a central lipophilic pocket in TEAD amenable to the small-molecule binding site of autopalmitoylation. Within this lipophilic palmitate pocket, post-translational S-palmitoylation of TEAD at a conserved catalytic cysteine (Cys) residue (e.g., C380) leads to TEAD stabilization and is believed to be critical for maintaining appropriate protein folding to enable the formation of the transcriptionally active YAP/TAZ -TEAD complex. Therefore, targeting the palmitate pocket with allosteric small molecules inhibitor disrupt the formation of the YAP/TAZ-TEAD complex and modulate YAP/TAZ-TEAD driven gene transcription. We have identified a series of novel, potent small-molecule inhibitors of the YAP/TAZ-TEAD transcriptional complex. It showed under 20 nM of potency in the inhibition of TEAD luciferase reporter assay in MCF7-TEAD-luc cells. These TEAD inhibitors inhibited YAP/TAZ-TEAD protein-protein interaction in H226 cells harboring neurofibromin 2 (NF2) alteration. In addition, our lead compounds exhibited dose-dependent growth inhibitory effects in Hippo pathway-altered cancer cell lines and reduced the YAP/TAZ-TEAD target gene expression, CTGF, and CYR61 in H226 cells. Our lead compounds, singled out and optimized based on in vitro functional assay, displayed favorable pharmacokinetic and safety profiles. Furthermore, orally administered lead compound effectively suppressed tumor growth within tolerable doses in xenograft mice with tumors harboring NF2 alteration as a major upstream molecule of the Hippo pathway. In summary, we pointed our novel YAP/TAZ-TEAD inhibitors that showed excellent efficacy in Hippo-altered mutant cancer in vitro and in vivo xenograft models. These data best support a therapeutic option for the treatment of cancers with amplified or overexpressed YAP, TAZ, or TEAD genes. Further preclinical studies will be performed and reported soon after the establishment of a preclinical candidate. Citation Format: Jisook Kim, Seung Hyun Jung, Seon Yeong Han, Jihee Yoon, Minjeong Kim, Jooyun Byun, Heesun Moon, Eunyoung Lee, Yu-Yon Kim, Hyunjin Park, So-Ye Jeon, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh. Antitumor activity of novel and potent YAP/TAZ-TEAD inhibitorstargeting the Hippo pathway in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1614.

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

The complete plastid genome and nuclear ribosomal transcription unit sequences of &lt;i&gt;Spiraea prunifolia&lt;/i&gt; f. &lt;i&gt;simpliciflora&lt;/i&gt; (Rosaceae)

&lt;i&gt;Spiraea prunifolia&lt;/i&gt; f. &lt;i&gt;simpliciflora&lt;/i&gt; Nakai is a perennial shrub widely used for horticultural and medicinal purposes. We simultaneously obtained the complete plastid genome (plastome) and nuclear ribosomal gene transcription units, 45S nuclear ribosomal DNA (nrDNA) and 5S nrDNA of &lt;i&gt;S. prunifolia&lt;/i&gt; f. &lt;i&gt;simpliciflora&lt;/i&gt;, using Illumina short-read data. The plastome is 155,984 bp in length with a canonical quadripartite structure consisting of 84,417 bp of a large single-copy region, 18,887 bp of a short single-copy region, and 26,340 bp of two inverted repeat regions. Overall, a total of 113 genes (79 protein-coding genes, 30 tRNAs, and four rRNAs) were annotated in the plastome. The 45S nrDNA transcription unit is 5,848 bp in length: 1,809 bp, 161 bp, and 3,397 bp for 18S, 5.8S, and 26S, respectively, and 261 bp and 220 bp for internal transcribed spacer (ITS) 1 and ITS 2 regions, respectively. The 5S nrDNA unit is 512 bp, including 121 bp of 5S rRNA and 391 bp of intergenic spacer regions. Phylogenetic analyses showed that the genus &lt;i&gt;Spiraea&lt;/i&gt; was monophyletic and sister to the clade of &lt;i&gt;Sibiraea angustata&lt;/i&gt;, &lt;i&gt;Petrophytum caespitosum&lt;/i&gt; and &lt;i&gt;Kelseya uniflora&lt;/i&gt;. Within the genus &lt;i&gt;Spiraea&lt;/i&gt;, the sections &lt;i&gt;Calospira&lt;/i&gt; and &lt;i&gt;Spiraea&lt;/i&gt; were monophyletic, but the sect. &lt;i&gt;Glomerati&lt;/i&gt; was nested within the sect. &lt;i&gt;Chamaedryon&lt;/i&gt;. In the sect. &lt;i&gt;Glomerati&lt;/i&gt;, &lt;i&gt;S. prunifolia&lt;/i&gt; f. &lt;i&gt;simpliciflora&lt;/i&gt; formed a subclade with &lt;i&gt;S. media&lt;/i&gt;, and the subclade was sister to &lt;i&gt;S. thunbergii&lt;/i&gt; and &lt;i&gt;S. mongolica&lt;/i&gt;. The close relationship between &lt;i&gt;S. prunifolia&lt;/i&gt; f. &lt;i&gt;simpliciflora&lt;/i&gt; and &lt;i&gt;S. media&lt;/i&gt; was also supported by the nrDNA phylogeny, indicating that the plastome and nrDNA sequences assembled in this study belong to the genus &lt;i&gt;Spiraea&lt;/i&gt;. The newly reported complete plastome and nrDNA transcription unit sequences of &lt;i&gt;S. prunifolia&lt;/i&gt; f. &lt;i&gt;simpliciflora&lt;/i&gt; provide useful information for further phylogenetic and evolutionary studies of the genus &lt;i&gt;Spiraea&lt;/i&gt;, as well as the family Rosaceae.

Light-activated macromolecular phase separation modulates transcription by reconfiguring chromatin interactions.

Biomolecular condensates participate in the regulation of gene transcription, yet the relationship between nuclear condensation and transcriptional activation remains elusive. Here, we devised a biotinylated CRISPR-dCas9-based optogenetic method, light-activated macromolecular phase separation (LAMPS), to enable inducible formation, affinity purification, and multiomic dissection of nuclear condensates at the targeted genomic loci. LAMPS-induced condensation at enhancers and promoters activates endogenous gene transcription by chromatin reconfiguration, causing increased chromatin accessibility and de novo formation of long-range chromosomal loops. Proteomic profiling of light-induced condensates by dCas9-mediated affinity purification uncovers multivalent interaction-dependent remodeling of macromolecular composition, resulting in the selective enrichment of transcriptional coactivators and chromatin structure proteins. Our findings support a model whereby the formation of nuclear condensates at native genomic loci reconfigures chromatin architecture and multiprotein assemblies to modulate gene transcription. Hence, LAMPS facilitates mechanistic interrogation of the relationship between nuclear condensation, genome structure, and gene transcription in living cells.

Inhibition of mitochondrial transcription by the neurotoxin MPP+

The neurotoxin MPP+ triggers cell death of dopamine neurons and induces Parkinson's disease symptoms in mice and men, but the immediate transcriptional response to this neurotoxin has not been studied. We therefore treated human SH-SY5Y cells with a low dose (0.1 mM) of MPP+ and measured the effect on nascent transcription by precision run-on sequencing (PRO-seq). We found that transcription of the mitochondrial genome was significantly reduced already after 30 min, whereas nuclear gene transcription was unaffected. Inhibition of respiratory complex I by MPP+ led to reduced ATP production, that may explain the diminished activity of mitochondrial RNA polymerase. Our results show that MPP+ has a direct effect on mitochondrial function and transcription, and that other gene expression or epigenetic changes induced by this neurotoxin are secondary effects that reflect a cellular adaptation program.

Serum Androgen Metabolites Correlate with Clinical Variables in African and European American Men with Localized, Therapy Naïve Prostate Cancer.

Dihydrotestosterone (DHT) and testosterone (T), which mediate androgen receptor nuclear translocation and target gene transcription, are crucial androgens and essential molecular triggers required for the proliferation and survival of prostate cancer cells. Therefore, androgen metabolism is commonly targeted in the treatment of prostate cancer. Using a high-pressure liquid chromatographic assay with tandem mass spectral detection, we determined the serum levels of metabolites produced during DHT/T biosynthesis in African American (AA) and European American (EA) men with localized, therapy naïve prostate cancer. Serum progesterone and related metabolites were significantly lower in AA men than in EA men, and these differences were associated with rapid disease progression. Multivariate analysis revealed significant differences between a subset of intermediate androgen metabolites between AA and EA men and between men with <=3 + 4 and >=4 + 3 Gleason score disease. AA men have a significantly higher frequency of single nucleotide polymorphisms in CYP11B1 and CYP11B2, enzymes that regulate corticosterone-aldosterone conversion. Finally, higher levels of T and pregnenolone were associated with a lower risk of progression-free survival only in AA men. This work provides new insight into androgen metabolism and racial disparities in prostate cancer by presenting evidence of dysregulated androgen biosynthesis in therapy naïve disease that correlates with clinical variables.

Dexamethasone and OLT1177 Cooperate in the Reduction of Melanoma Growth by Inhibiting STAT3 Functions.

The NLRP3 inflammasome is a multimolecular complex that processes inactive IL-1β and IL-18 into proinflammatory cytokines. OLT1177 is an orally active small compound that specifically inhibits NLRP3. Here, B16F10 melanoma were implanted in mice and treated with OLT1177 as well as combined with the glucocorticoid dexamethasone. At sacrifice, OLT1177 treated mice had significantly smaller tumors compared to tumor-bearing mice treated with vehicle. However, the combined treatment of OLT1177 plus dexamethasone revealed a greater suppression of tumor growth. This reduction was accompanied by a downregulation of nuclear and mitochondrial STAT3-dependent gene transcription and by a significant reduction of STAT3 Y705 and S727 phosphorylations in the tumors. In vitro, the human melanoma cell line 1205Lu, stimulated with IL-1α, exhibited significantly lower levels of STAT3 Y705 phosphorylation by the combination treatment, thus affecting the nuclear functions of STAT3. In the same cells, STAT3 serine 727 phosphorylation was also lower, affecting the mitochondrial functions of STAT3. In addition, metabolic analyses revealed a marked reduction of ATP production rate and glycolytic reserve in cells treated with the combination of OLT1177 plus dexamethasone. These findings demonstrate that the combination of OLT1177 and dexamethasone reduces tumor growth by targeting nuclear as well as mitochondrial functions of STAT3.

Ubiquitin-specific protease 11 promotes partial epithelial-to-mesenchymal transition by deubiquitinating the epidermal growth factor receptor during kidney fibrosis

The aberrant expression of ubiquitin-specific protease 11 (USP11) is believed to be related to tumor progression. However, few studies have reported the biological function and clinical importance of USP11 in kidney fibrosis. Here, we demonstrated USP11 was highly upregulated in the kidneys from patients with chronic kidney disease and correlated positively with fibrotic lesion but negatively with kidney function. Conditional USP11 deletion or pharmacologic inhibition with Mitoxantrone attenuated pathological lesions and improved kidney function in both hyperuricemic nephropathy (HN)- and folic acid (FA)-induced mouse models of kidney fibrosis. Mechanistically, by RNA sequencing, USP11 was found to be involved in nuclear gene transcription of the epidermal growth factor receptor (EGFR). USP11 co-immunoprecipitated and co-stained with extra-nuclear EGFR and deubiquitinated and protected EGFR from proteasome-dependent degradation. Genetic or pharmacological depletion of USP11 facilitated EGFR degradation and abated augmentation of TGF-β1 and downstream signaling. This consequently alleviated the partial epithelial-mesenchymal transition, G2/M arrest and aberrant secretome of profibrogenic and proinflammatory factors in uric acid-stimulated tubular epithelial cells. Moreover, USP11 deletion had anti-fibrotic and anti-inflammatory kidney effects in the murine HN and FA models. Thus, our study provides evidence supporting USP11 as a promising target for minimizing kidney fibrosis and that inhibition of USP11 has potential to be an effective strategy for patients with chronic kidney disease.

The emergent role of mitochondrial surveillance in cellular health.

Mitochondrial dysfunction is one of the primary causatives for many pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and aging. Decline in mitochondrial functions leads to the loss of proteostasis, accumulation of ROS, and mitochondrial DNA damage, which further exacerbates mitochondrial deterioration in a vicious cycle. Surveillance mechanisms, in which mitochondrial functions are closely monitored for any sign of perturbations, exist to anticipate possible havoc within these multifunctional organelles with primitive origin. Various indicators of unhealthy mitochondria, including halted protein import, dissipated membrane potential, and increased loads of oxidative damage, are on the top of the lists for close monitoring. Recent research also indicates a possibility of reductive stress being monitored as part of a mitochondrial surveillance program. Upon detection of mitochondrial stress, multiple mitochondrial stress-responsive pathways are activated to promote the transcription of numerous nuclear genes to ameliorate mitochondrial damage and restore compromised cellular functions. Co-expression occurs through functionalization of transcription factors, allowing their binding to promoter elements to initiate transcription of target genes. This review provides a comprehensive summary of the intricacy of mitochondrial surveillance programs and highlights their roles in our cellular life. Ultimately, a better understanding of these surveillance mechanisms is expected to improve healthspan.

H4 acetylation by the NuA4 complex is required for plastid transcription and chloroplast biogenesis

Chloroplast biogenesis is crucial in plant development, as it is essential for the transition to autotrophic growth. This process is light-induced and relies on the orchestrated transcription of nuclear and plastid genes, enabling the effective assembly and regulation of the photosynthetic machinery. Here we reveal a new regulation level for this process by showing the involvement of chromatin remodelling in the nuclear control of plastid gene expression for proper chloroplast biogenesis and function. The two Arabidopsis homologues of yeast EPL1 protein, components of the NuA4 histone acetyltransferase complex, are essential for plastid transcription and correct chloroplast development and performance. We show that EPL1 proteins are light-regulated and necessary for concerted expression of nuclear genes encoding most components of chloroplast transcriptional machinery, directly mediating H4K5ac deposition at these loci and promoting the expression of plastid genes required for chloroplast biogenesis. These data unveil a NuA4-mediated mechanism regulating chloroplast biogenesis that links the transcription of nuclear and plastid genomes during chloroplast development.

Signal Transduction and Gene Regulation in the Endothelium.

Extracellular signals act on G-protein-coupled receptors (GPCRs) to regulate homeostasis and adapt to stress. This involves rapid intracellular post-translational responses and long-lasting gene-expression changes that ultimately determine cellular phenotype and fate changes. The lipid mediator sphingosine 1-phosphate (S1P) and its receptors (S1PRs) are examples of well-studied GPCR signaling axis essential for vascular development, homeostasis, and diseases. The biochemical cascades involved in rapid S1P signaling are well understood. However, gene-expression regulation by S1PRs are less understood. In this review, we focus our attention to how S1PRs regulate nuclear chromatin changes and gene transcription to modulate vascular and lymphatic endothelial phenotypic changes during embryonic development and adult homeostasis. Because S1PR-targeted drugs approved for use in the treatment of autoimmune diseases cause substantial vascular-related adverse events, these findings are critical not only for general understanding of stimulus-evoked gene regulation in the vascular endothelium, but also for therapeutic development of drugs for autoimmune and perhaps vascular diseases.