-
BioRxiv : the Preprint Server For... Jun 2024In most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that...
In most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that gave rise to modern mitochondria. Mitochondrial genomes are dramatically reduced in their gene content due to the process of endosymbiotic gene transfer to the nucleus; as a result most mitochondrial proteins are encoded in the nucleus and imported into mitochondria. This includes the components of the dedicated mitochondrial transcription and replication systems and regulatory factors, which are entirely distinct from the information processing systems in the nucleus. However, since the 1990s several nuclear transcription factors have been reported to act in mitochondria, and previously we identified 8 human and 3 mouse transcription factors (TFs) with strong localized enrichment over the mitochondrial genome using ChIP-seq (Chromatin Immunoprecipitation) datasets from the second phase of the ENCODE (Encyclopedia of DNA Elements) Project Consortium. Here, we analyze the greatly expanded in the intervening decade ENCODE compendium of TF ChIP-seq datasets (a total of 6,153 ChIP experiments for 942 proteins, of which 763 are sequence-specific TFs) combined with interpretative deep learning models of TF occupancy to create a comprehensive compendium of nuclear TFs that show evidence of association with the mitochondrial genome. We find some evidence for chrM occupancy for 50 nuclear TFs and two other proteins, with bZIP TFs emerging as most likely to be playing a role in mitochondria. However, we also observe that in cases where the same TF has been assayed with multiple antibodies and ChIP protocols, evidence for its chrM occupancy is not always reproducible. In the light of these findings, we discuss the evidential criteria for establishing chrM occupancy and reevaluate the overall compendium of putative mitochondrial-acting nuclear TFs.
PubMed: 38895386
DOI: 10.1101/2024.06.04.597442 -
Frontiers in Aging Neuroscience 2024Now, there are no sensitive biomarkers for improving Alzheimer's disease (AD) and comorbid Parkinson's disease (PD). The aim of the present study was to analyze...
BACKGROUND
Now, there are no sensitive biomarkers for improving Alzheimer's disease (AD) and comorbid Parkinson's disease (PD). The aim of the present study was to analyze differentially expressed genes (DEGs) in brain tissue from AD and PD patients via bioinformatics analysis, as well as to explore precise diagnostic and therapeutic targets for AD and comorbid PD.
METHODS
GFE122063 and GSE7621 data sets from GEO in NCBI, were used to screen differentially expressed genes (DEGs) for AD and PD, and identify the intersected genes, respectively. Intersected genes were analyzed by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then, STRING site and Cytoscape were used to construct a protein-protein interaction (PPI) network, CytoNCA algorithm to analyze and evaluate centrality, Mcode plug-in to analyze module, and Cytohubba to screen key genes. Combined GO-KEGG enrichment analysis with Cytoscape algorithm to screen the key gene in AD complicated with PD. Then, the DEGs for AD and PD were imported into the Association Map (CMap) online platform to screen out the top 10 small molecule drugs, and using molecular docking techniques to evaluate the interactions between small molecule drugs and key genes receptors.
RESULTS
In total, 231 upregulated genes and 300 downregulated genes were identified. GO analysis revealed that the DEGs were highly enriched in signal transduction, and KEGG analysis revealed that the DEGs were associated with the MAPK and PI3K-Akt signaling pathways. Epidermal growth factor receptor (EGFR) was identified as a potential receptor gene in AD and comorbid PD. EGFR was upregulated in both AD and PD, and the proteins that interact with EGFR were enriched in the Ras/Raf/MAPK and PI3K/Akt signaling pathways. Semagacestat was identified as a drug with therapeutic potential for treating AD complicated with PD. There was a high binding affinity between semagacestat and EGFR, with seven hydrogen bonds and one hydrophobic bond.
DISCUSSION
Semagacestat may improve the health of patients with AD complicated with PD through the regulation of the Ras/Raf/MAPK and PI3K/Akt signaling pathways by EGFR, providing evidence supporting the structural modification of semagacestat to develop a more effective drug for treating AD complicated with PD.
PubMed: 38894850
DOI: 10.3389/fnagi.2024.1411320 -
Nutrients May 2024Blood selenium (Se) concentrations differ substantially by population and could be influenced by genetic variants, increasing Se deficiency-related diseases. We...
Blood selenium (Se) concentrations differ substantially by population and could be influenced by genetic variants, increasing Se deficiency-related diseases. We conducted a genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with serum Se deficiency in 382 adults with admixed ancestry. Genotyping arrays were combined to yield 90,937 SNPs. R packages were applied to quality control and imputation. We also performed the ancestral proportion analysis. The Search Tool for the Retrieval of Interacting Genes was used to interrogate known protein-protein interaction networks (PPIs). Our ancestral proportion analysis estimated 71% of the genome was from Caucasians, 22% was from Africans, and 8% was from East Asians. We identified the SNP rs1561573 in the TraB domain containing 2B (), rs425664 in MAF bZIP transcription factor (), rs10444656 in spermatogenesis-associated 13 (), and rs6592284 in heat shock protein nuclear import factor () genes. The PPI analysis showed functional associations of Se deficiency, thyroid hormone metabolism, NRF2-ARE and the Wnt pathway, and heat stress. Our findings show evidence of a genetic association between Se deficiency and metabolic pathways indirectly linked to Se regulation, reinforcing the complex relationship between Se intake and the endogenous factors affecting the Se requirements for optimal health.
Topics: Humans; Selenium; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Male; Female; Adult; Brazil; Middle Aged; Genetic Predisposition to Disease; White People; Genotype; Protein Interaction Maps
PubMed: 38892560
DOI: 10.3390/nu16111627 -
International Journal of Molecular... May 2024Skeletal muscle grows in response to a combination of genetic and environmental factors, and its growth and development influence the quality of pork. Elucidating the...
Skeletal muscle grows in response to a combination of genetic and environmental factors, and its growth and development influence the quality of pork. Elucidating the molecular mechanisms regulating the growth and development of skeletal muscle is of great significance to both animal husbandry and farm management. The is an excellent pig breed based on the original , importing the genes of the for meat traits, and cultivated through years of scientific selection and breeding. In this study, full-length transcriptome sequencing was performed on three growth stages of , aiming to study the developmental changes in at different developmental stages at the molecular level and to screen the key genes affecting the growth of skeletal muscle in . We performed an enrichment analysis of genes showing differential expression and constructed a protein-protein interaction network with the aim of identifying core genes involved in the development of . Notably, genes such as , , , and may be potential regulators of muscle development in . Our results contribute to the understanding of the molecular mechanisms of skeletal muscle development in this pig breed, which will facilitate molecular breeding efforts and the development of pig breeds to meet the needs of the livestock industry.
Topics: Animals; Muscle, Skeletal; Swine; Gene Expression Profiling; Transcriptome; Gene Expression Regulation, Developmental; Muscle Development; Breeding; Protein Interaction Maps
PubMed: 38892283
DOI: 10.3390/ijms25116095 -
Liver International : Official Journal... Jun 2024Heme is a primordial macrocycle upon which most aerobic life on Earth depends. It is essential to the survival and health of nearly all cells, functioning as a... (Review)
Review
Heme is a primordial macrocycle upon which most aerobic life on Earth depends. It is essential to the survival and health of nearly all cells, functioning as a prosthetic group for oxygen-carrying proteins and enzymes involved in oxidation/reduction and electron transport reactions. Heme is essential for the function of numerous hemoproteins and has numerous other roles in the biochemistry of life. In mammals, heme is synthesised from glycine, succinyl-CoA, and ferrous iron in a series of eight steps. The first and normally rate-controlling step is catalysed by 5-aminolevulinate synthase (ALAS), which has two forms: ALAS1 is the housekeeping form with highly variable expression, depending upon the supply of the end-product heme, which acts to repress its activity; ALAS2 is the erythroid form, which is regulated chiefly by the adequacy of iron for erythroid haemoglobin synthesis. Abnormalities in the several enzymes of the heme synthetic pathway, most of which are inherited partial enzyme deficiencies, give rise to rare diseases called porphyrias. The existence and role of heme importers and exporters in mammals have been debated. Recent evidence established the presence of heme transporters. Such transporters are important for the transfer of heme from mitochondria, where the penultimate and ultimate steps of heme synthesis occur, and for the transfer of heme from cytoplasm to other cellular organelles. Several chaperones of heme and iron are known and important for cell health. Heme and iron, although promoters of oxidative stress and potentially toxic, are essential cofactors for cellular energy production and oxygenation.
PubMed: 38888238
DOI: 10.1111/liv.15965 -
Journal of Ethnopharmacology Jun 2024Ginseng Radix and Astragali Radix are commonly combined to tonify Qi and alleviate fatigue. Previous studies have employed biological networks to investigate the...
ETHNOPHARMACOLOGICAL RELEVANCE
Ginseng Radix and Astragali Radix are commonly combined to tonify Qi and alleviate fatigue. Previous studies have employed biological networks to investigate the mechanisms of herb pairs in treating different diseases. However, these studies have only elucidated a single network for each herb pair, without emphasizing the superiority of the herb combination over individual herbs.
AIM OF THE STUDY
This study proposes an approach of comparing biological networks to highlight the synergistic effect of the pair in treating cancer-related fatigue (CRF).
METHODS
The compounds and targets of Ginseng Radix, Astragali Radix, and CRF diseases were collected and predicted using different databases. Subsequently, the overlapping targets between herbs and disease were imported into the STRING and DAVID tools to build protein-protein interaction (PPI) networks and analyze enriched KEGG pathways. The biological networks of Ginseng Radix and Astragali Radix were compared separately or together using the DyNet application. Molecular docking was used to verify the predicted results. Further, in vitro experiments were conducted to validate the synergistic pathways identified in in silico studies.
RESULTS
In the PPI network comparison, the combination created 89 new interactions and an increased average degree (11.260) when compared to single herbs (10.296 and 9.394). The new interactions concentrated on HRAS, STAT3, JUN, and IL6. The topological analysis identified 20 core targets of the combination, including three Ginseng Radix-specific targets, three Astragali Radix-specific targets, and 14 shared targets. In KEGG enrichment analysis, the combination regulated additional signaling pathways (152) more than Ginseng Radix (146) and Astragali Radix (134) alone. The targets of the herb pair synergistically regulated cancer pathways, specifically hypoxia-inducible factor 1 (HIF-1) signaling pathway. In vitro experiments including enzyme-linked immunosorbent assay and western blot demonstrated that two herbs combination could up-regulate HIF-1α signaling pathway at different combined concentrations compared to either single herb alone.
CONCLUSION
The herb pair increased protein interactions and adjusted metabolic pathways more than single herbs. This study provides insights into the combination of Ginseng Radix and Astragali Radix in clinical practice.
PubMed: 38885914
DOI: 10.1016/j.jep.2024.118447 -
Frontiers in Cell and Developmental... 2024Mitochondria are key organelles for the optimal function of the cell. Among their many functions, they maintain protein homeostasis through their own proteostatic... (Review)
Review
Mitochondria are key organelles for the optimal function of the cell. Among their many functions, they maintain protein homeostasis through their own proteostatic machinery, which involves proteases and chaperones that regulate protein import and folding inside mitochondria. In the early 2000s, the mitochondrial unfolded protein response (UPR) was first described in mammalian cells. This stress response is activated by the accumulation of unfolded/misfolded proteins within the mitochondrial matrix, which results in the transmission of a signal to the nucleus to increase the expression of proteases and chaperones to address the abnormal mitochondrial protein load. After its discovery, this retrograde signaling pathway has also been described in other organisms of different complexities, suggesting that it is a conserved stress response. Although there are some specific differences among organisms, the mechanism of this stress response is mostly similar and involves the transmission of a signal from mitochondria to the nucleus that induces chromatin remodeling to allow the binding of specific transcription factors to the promoters of chaperones and proteases. In the last decade, proteins and signaling pathways that could be involved in the regulation of the UPR, including the Wnt signaling pathway, have been described. This minireview aims to summarize what is known about the mechanism of the UPR and its regulation, specifically in mammals and .
PubMed: 38882057
DOI: 10.3389/fcell.2024.1405393 -
The Journal of General and Applied... Jun 2024Gene expression controllers are useful tools for microbial production of recombinant proteins and valued bio-based chemicals. Despite its usefulness, they have rarely...
Gene expression controllers are useful tools for microbial production of recombinant proteins and valued bio-based chemicals. Despite its usefulness, they have rarely been applied to the practical industrial bioprocess, due to the lack of systems that meets the three requirements: low cost, safety, and tight control, to the inducer molecules. Previously, we have developed the high-spec gene induction system controlled by safe and cheap inducer choline. However, the system requires relatively high concentration (~100 mM) of choline to fully induce the gene under control. In this work, we attempted to drastically improve the sensitivity of this induction system to further reduce the induction costs. To this end, we devised a simple circuit which couple gene induction system with positive-feedback loop (P-loop) of choline importer protein BetT. After the tuning of translation level of BetT (strength of the P-loop) and deletion of endogenous betI (noise sources), highly active yet stringent control of gene expression was achieved using about 100 times less amount of inducer molecules. The choline induction system developed in this study has the lowest basal expression, the lowest choline needed to be activated, and the highest amplitude of induction as the highest available promoter such as those known as P system. With this system, one can tightly control the expression level of genes of interest with negligible cost for inducer molecule, which has been the bottleneck for the application to the large-scale industrial processes.
PubMed: 38880610
DOI: 10.2323/jgam.2024.05.004 -
Experimental Hematology Jun 2024Transcriptional mechanisms establish and maintain complex genetic and protein networks to control cell state transitions. The hematopoietic transcription factor GATA1 is... (Review)
Review
Transcriptional mechanisms establish and maintain complex genetic and protein networks to control cell state transitions. The hematopoietic transcription factor GATA1 is a master regulator of erythropoiesis and megakaryopoiesis, and human GATA1genetic variants cause anemia and megakaryoblastic leukemia. Multiomic analyses revealed that GATA1 controls expression of transporters and metabolic enzymes that dictate intracellular levels of endogenous small molecules, including heme, metal ions, and sphingolipids. Besides its canonical function as a hemoglobin component, heme facilitates or antagonizes GATA1 function to regulate erythropoiesis via mechanisms dependent or independent of the heme-binding transcription factor BTB domain and CNC homology 1 (BACH1). GATA1 regulates the expression of genes encoding heme biosynthetic enzymes and BACH1. GATA1 maintains homeostasis of bioactive ceramides during erythroid differentiation by regulating genes encoding sphingolipid metabolic enzymes. Disrupting ceramide homeostasis impairs critical cytokine signaling and is detrimental to erythroid cells. During erythroid maturation, GATA1 induces a zinc transporter switch that favors export versus import, thus dictating the intracellular zinc level, erythroblast survival, and differentiation. In aggregate, these studies support an emerging paradigm in which GATA factor-dependent transcriptional mechanisms control the intracellular levels of endogenous small molecules and small molecule-dependent feedback loops that serve as vital effectors of transcription factor activity, genome function, and cell state transitions.
PubMed: 38876253
DOI: 10.1016/j.exphem.2024.104252 -
PLoS Pathogens Jun 2024Influenza viruses transcribe and replicate their genome in the nucleus of the infected cells, two functions that are supported by the viral RNA-dependent RNA-polymerase...
Influenza viruses transcribe and replicate their genome in the nucleus of the infected cells, two functions that are supported by the viral RNA-dependent RNA-polymerase (FluPol). FluPol displays structural flexibility related to distinct functional states, from an inactive form to conformations competent for replication and transcription. FluPol machinery is constituted by a structurally-invariant core comprising the PB1 subunit stabilized with PA and PB2 domains, whereas the PA endonuclease and PB2 C-domains can pack in different configurations around the core. To get insights into the functioning of FluPol, we selected single-domain nanobodies (VHHs) specific of the influenza A FluPol core. When expressed intracellularly, some of them exhibited inhibitory activity on type A FluPol, but not on the type B one. The most potent VHH (VHH16) binds PA and the PA-PB1 dimer with an affinity below the nanomolar range. Ectopic intracellular expression of VHH16 in virus permissive cells blocks multiplication of different influenza A subtypes, even when induced at late times post-infection. VHH16 was found to interfere with the transport of the PA-PB1 dimer to the nucleus, without affecting its handling by the importin β RanBP5 and subsequent steps in FluPol assembly. Using FluPol mutants selected after passaging in VHH16-expressing cells, we identified the VHH16 binding site at the interface formed by PA residues with the N-terminus of PB1, overlapping or close to binding sites of two host proteins, ANP32A and RNA-polymerase II RPB1 subunit which are critical for virus replication and transcription, respectively. These data suggest that the VHH16 neutralization is likely due to several activities, altering the import of the PA-PB1 dimer into the nucleus as well as inhibiting specifically virus transcription and replication. Thus, the VHH16 binding site represents a new Achilles' heel for FluPol and as such, a potential target for antiviral development.
Topics: Single-Domain Antibodies; Humans; Antiviral Agents; Influenza A virus; Virus Replication; Animals; RNA-Dependent RNA Polymerase; Viral Proteins; Influenza, Human; HEK293 Cells; Dogs; Madin Darby Canine Kidney Cells
PubMed: 38875296
DOI: 10.1371/journal.ppat.1011642