bims-miholp Biomed News
on Mitochondria, hormesis and lifespan programming
Issue of 2024–06–09
eleven papers selected by
Guillermo Martínez Corrales, Institut de Biologia Molecular de Barcelona
  1. Xbp1 targets canonical UPRER and non-canonical pathways in separate tissues to promote longevity.
  2. The age-dependent regulation of pancreatic islet landscape is fueled by a HNF1a-immune signaling loop.
  3. Target gene responses differ when transcription factor levels are acutely decreased by nuclear export versus degradation.
  4. Genome-wide nucleosome and transcription factor responses to genetic perturbations reveal chromatin-mediated mechanisms of transcriptional regulation.
  5. The human gut microbiome and aging.
  6. Transcription Factor Binding Site Prediction Using CnNet Approach.
  7. The heat shock response as a condensate cascade.
  8. Collaboration between distinct SWI/SNF chromatin remodeling complexes directs enhancer selection and activation of macrophage inflammatory genes.
  9. Longevity factor FOXO3a: A potential therapeutic target for age-related ocular diseases.
  10. Malnutrition: From Mother to Child.
  11. Histone acylation at a glance.
  1. iScience. 2024 Jun 21. 27(6): 109962
    Xbp1 targets canonical UPRER and non-canonical pathways in separate tissues to promote longevity.
    Mengjia Li, Haocheng Shou, Guillermo Martínez Corrales, Tatiana Svermova, Alessandra Vieira Franco, Nazif Alic.
      Transcription factors can reprogram gene expression to promote longevity. Here, we investigate the role of Drosophila Xbp1. Xbp1 is activated by splicing of its primary transcript, Xbp1u, to generate Xbp1s, a key activator of the endoplasmic reticulum unfolded protein response (UPRER). We show that Xbp1s induces the conical UPRER in the gut, promoting longevity from the resident stem cells. In contrast, in the fat body, Xbp1s does not appear to trigger UPRER but alters metabolic gene expression and is still able to extend lifespan. In the fat body, Xbp1s and dFOXO impinge on the same target genes, including the PGC-1α orthologue Srl, and dfoxo requires Xbp1 to extend lifespan. Interestingly, unspliceable version of the Xbp1 mRNA, Xbp1u can also extend lifespan, hinting at roles in longevity for the poorly characterized Xbp1u transcription factor. These findings reveal the diverse functions of Xbp1 in longevity in the fruit fly.
    Keywords:  Biological sciences; Molecular biology; Molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2024.109962
  2. Mech Ageing Dev. 2024 May 31. pii: S0047-6374(24)00051-4. [Epub ahead of print]220 111951
    The age-dependent regulation of pancreatic islet landscape is fueled by a HNF1a-immune signaling loop.
    Andreas Frøslev Mathisen, Thomas Aga Legøy, Ulrik Larsen, Lucas Unger, Shadab Abadpour, Joao A Paulo, Hanne Scholz, Luiza Ghila, Simona Chera.
      Animal longevity is a function of global vital organ functionality and, consequently, a complex polygenic trait. Yet, monogenic regulators controlling overall or organ-specific ageing exist, owing their conservation to their function in growth and development. Here, by using pathway analysis combined with wet-biology methods on several dynamic timelines, we identified Hnf1a as a novel master regulator of the maturation and ageing in the adult pancreatic islet during the first year of life. Conditional transgenic mice bearing suboptimal levels of this transcription factor in the pancreatic islets displayed age-dependent changes, with a profile echoing precocious maturation. Additionally, the comparative pathway analysis revealed a link between Hnf1a age-dependent regulation and immune signaling, which was confirmed in the ageing timeline of an overly immunodeficient mouse model. Last, the global proteome analysis of human islets spanning three decades of life largely backed the age-specific regulation observed in mice. Collectively, our results suggest a novel role of Hnf1a as a monogenic regulator of the maturation and ageing process in the pancreatic islet via a direct or indirect regulatory loop with immune signaling.
    Keywords:  HNF1A; Immune response; Islet ageing; Pancreatic islets; Pathway analysis
    DOI:  https://doi.org/10.1016/j.mad.2024.111951
  3. bioRxiv. 2024 May 20. pii: 2024.05.20.595009. [Epub ahead of print]
    Target gene responses differ when transcription factor levels are acutely decreased by nuclear export versus degradation.
    James McGehee, Angelike Stathopoulos.
      Defining the time of action for morphogens requires tools capable of temporally controlled perturbations. To study how the transcription factor Dorsal affects patterning of the Drosophila embryonic dorsal-ventral axis, we used two light-inducible tags that result in either nuclear export or degradation of Dorsal when exposed to blue light. Nuclear export of Dorsal results in loss of expression for the high threshold, ventrally-expressed target gene snail ( sna ) but retention of the low threshold, laterally-expressed target gene short-gastrulation ( sog ). In contrast, degradation of Dorsal results in retention of sna, loss of sog , and lower nuclear levels than when Dorsal is exported from the nucleus. To elucidate how nuclear export results in loss of sna but degradation does not, we investigated Dorsal kinetics using photobleaching and found it reenters the nucleus even under conditions of blue-light when export is favored. The associated kinetics of being imported and exported continuously are likely responsible for loss of sna but, alternatively, can support sog . Collectively, our results show that this dynamic patterning process is influenced by both Dorsal concentration and nuclear retention.
    SUMMARY STATEMENT: This study shows how optogenetic tools can be used to determine how a transcription factor's levels and nuclear retention impact a dynamic patterning process.
    DOI:  https://doi.org/10.1101/2024.05.20.595009
  4. bioRxiv. 2024 May 26. pii: 2024.05.24.595391. [Epub ahead of print]
    Genome-wide nucleosome and transcription factor responses to genetic perturbations reveal chromatin-mediated mechanisms of transcriptional regulation.
    Kevin Moyung, Yulong Li, Alexander J Hartemink, David M MacAlpine.
      Epigenetic mechanisms contribute to gene regulation by altering chromatin accessibility through changes in transcription factor (TF) and nucleosome occupancy throughout the genome. Despite numerous studies focusing on changes in gene expression, the intricate chromatin-mediated regulatory code remains largely unexplored on a comprehensive scale. We address this by employing a factor-agnostic, reverse-genetics approach that uses MNase-seq to capture genome-wide TF and nucleosome occupancies in response to the individual deletion of 201 transcriptional regulators in Saccharomyces cerevisiae, thereby assaying nearly one million mutant-gene interactions. We develop a principled approach to identify and quantify chromatin changes genome-wide, observing differences in TF and nucleosome occupancy that recapitulate well-established pathways identified by gene expression data. We also discover distinct chromatin signatures associated with the up- and downregulation of genes, and use these signatures to reveal regulatory mechanisms previously unexplored in expression-based studies. Finally, we demonstrate that chromatin features are predictive of transcriptional activity and leverage these features to reconstruct chromatin-based transcriptional regulatory networks. Overall, these results illustrate the power of an approach combining genetic perturbation with high-resolution epigenomic profiling; the latter enables a close examination of the interplay between TFs and nucleosomes genome-wide, providing a deeper, more mechanistic understanding of the complex relationship between chromatin organization and transcription.
    DOI:  https://doi.org/10.1101/2024.05.24.595391
  5. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2359677
    The human gut microbiome and aging.
    Evan Bradley, John Haran.
      The composition of the human gut microbiome has been observed to change over the course of an individual's life. From birth, it is shaped by mode of delivery, diet, environmental exposures, geographic location, exposures to medications, and by aging itself. Here, we present a narrative review of the gut microbiome across the lifespan with a focus on its impacts on aging and age-related diseases in humans. We will describe how it is shaped, and features of the gut microbiome that have been associated with diseases at different phases of life and how this can adversely affect healthy aging. Across the lifespan, and especially in old age, a diverse microbiome that includes organisms suspected to produce anti-inflammatory metabolites such as short-chain fatty acids, has been reported to be associated with healthy aging. These findings have been remarkably consistent across geographic regions of the world suggesting that they could be universal features of healthy aging across all cultures and genetic backgrounds. Exactly how these features of the microbiome affect biologic processes associated with aging thus promoting healthy aging will be crucial to targeting the gut microbiome for interventions that will support health and longevity.
    Keywords:  Gut microbiome; age-related disease; aging; microbiome-based theraputics
    DOI:  https://doi.org/10.1080/19490976.2024.2359677
  6. IEEE/ACM Trans Comput Biol Bioinform. 2024 Jun 07. PP
    Transcription Factor Binding Site Prediction Using CnNet Approach.
    Mohamed Divan Masood, Manjula, Vijayan Sugumaran.
      Controlling the gene expression is the most important development in a living organism, which makes it easier to find different kinds of diseases and their causes. It's very difficult to know what factors control the gene expression. Transcription Factor (TF) is a protein that plays an important role in gene expression. Discovering the transcription factor has immense biological significance, however, it is challenging to develop novel techniques and evaluation for regulatory developments in biological structures. In this research, we mainly focus on 'sequence specificities' that can be ascertained from experimental data with 'deep learning' techniques, which offer a scalable, flexible and unified computational approach for predicting transcription factor binding. Specifically, Multiple Expression motifs for Motif Elicitation (MEME) technique with Convolution Neural Network (CNN) named as CnNet, has been used for discovering the 'sequence specificities' of DNA gene sequences dataset. This process involves two steps: a) discovering the motifs that are capable of identifying useful TF binding site by using MEME technique, and b) computing a score indicating the likelihood of a given sequence being a useful binding site by using CNN technique. The proposed CnNet approach predicts the TF binding score with much better accuracy compared to existing approaches. The source code and datasets used in this work are available at https://github.com/masoodbai/CnNet-Approach-for-TFBS.git.
    DOI:  https://doi.org/10.1109/TCBB.2024.3411024
  7. J Mol Biol. 2024 Jun 05. pii: S0022-2836(24)00237-7. [Epub ahead of print] 168642
    The heat shock response as a condensate cascade.
    Annisa Dea, David Pincus.
      The heat shock response (HSR) is a gene regulatory program controlling expression of molecular chaperones implicated in aging, cancer, and neurodegenerative disease. Long presumed to be activated by toxic protein aggregates, recent work suggests a new functional paradigm for the HSR in yeast. Rather than toxic aggregates, adaptive biomolecular condensates comprised of orphan ribosomal proteins (oRP) and stress granule components have been shown to be physiological chaperone clients. By titrating away the chaperones Sis1 and Hsp70 from the transcription factor Hsf1, these condensates activate the HSR. Upon release from Hsp70, Hsf1 forms spatially distinct transcriptional condensates that drive high expression of HSR genes. In this manner, the negative feedback loop controlling HSR activity - in which Hsf1 induces Hsp70 expression and Hsp70 represses Hsf1 activity - is embedded in the biophysics of the system. By analogy to phosphorylation cascades that transmit information via the dynamic activity of kinases, we propose that the HSR is organized as a condensate cascade that transmits information via the localized activity of molecular chaperones.
    DOI:  https://doi.org/10.1016/j.jmb.2024.168642
  8. Immunity. 2024 May 29. pii: S1074-7613(24)00262-0. [Epub ahead of print]
    Collaboration between distinct SWI/SNF chromatin remodeling complexes directs enhancer selection and activation of macrophage inflammatory genes.
    Jingwen Liao, Josephine Ho, Mannix Burns, Emily C Dykhuizen, Diana C Hargreaves.
      Macrophages elicit immune responses to pathogens through induction of inflammatory genes. Here, we examined the role of three variants of the SWI/SNF nucleosome remodeling complex-cBAF, ncBAF, and PBAF-in the macrophage response to bacterial endotoxin (lipid A). All three SWI/SNF variants were prebound in macrophages and retargeted to genomic sites undergoing changes in chromatin accessibility following stimulation. Cooperative binding of all three variants associated with de novo chromatin opening and latent enhancer activation. Isolated binding of ncBAF and PBAF, in contrast, associated with activation and repression of active enhancers, respectively. Chemical and genetic perturbations of variant-specific subunits revealed pathway-specific regulation in the activation of lipid A response genes, corresponding to requirement for cBAF and ncBAF in inflammatory and interferon-stimulated gene (ISG) activation, respectively, consistent with differential engagement of SWI/SNF variants by signal-responsive transcription factors. Thus, functional diversity among SWI/SNF variants enables increased regulatory control of innate immune transcriptional programs, with potential for specific therapeutic targeting.
    Keywords:  ARID1A; BAF complex; BRD9; SWI/SNF complex; TLR; chromatin remodeling; enhancer; inflammation; macrophage; toll like receptor; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.immuni.2024.05.008
  9. Life Sci. 2024 Jun 05. pii: S0024-3205(24)00359-X. [Epub ahead of print] 122769
    Longevity factor FOXO3a: A potential therapeutic target for age-related ocular diseases.
    Xiao-Dan Hao, Jin-Xiu Liu, Jing-Sai Zhang.
      The forkhead box protein O3 (FOXO3a) belongs to the subgroup O of the forkhead transcription factor family and plays an important role in regulating the aging process by participating in the regulation of various life processes, including cell cycle arrest, apoptosis, autophagy, oxidative stress, and DNA repair. The eye is an organ that is affected by aging earlier. However, the functional role and potential clinical applications of FOXO3a in age-related eye diseases have not received widespread attention and lacked comprehensive and clear clarification. In this review, we demonstrated the relationship between FOXO3a and visual system health, summarized the functional roles of FOXO3a in various eye diseases, and potential ocular-related therapies and drugs targeting FOXO3a in visual system diseases through a review and summary of relevant literature. This review indicates that FOXO3a is an important factor in maintaining the normal function of various tissues in the eye, and is closely related to the occurrence and development of ophthalmic-related diseases. Based on its vital role in the normal function of the visual system, FOXO3a has potential clinical application value in related ophthalmic diseases. At present, multiple molecules and drugs targeting FOXO3a have been reported to have the potential for the treatment of related ophthalmic diseases, but further clinical trials are needed. In conclusion, this review can facilitate us to grasp the role of FOXO3a in the visual system and provide new views and bases for the treatment strategy research of age-related eye diseases.
    Keywords:  Age-related eye diseases; Apoptosis; Autophagy; Forkhead box protein O3; Oxidative stress
    DOI:  https://doi.org/10.1016/j.lfs.2024.122769
  10. Am J Trop Med Hyg. 2024 Jun 04. pii: tpmd240012. [Epub ahead of print]
    Malnutrition: From Mother to Child.
    William A Petri, Jennifer Hendrick, Rashidul Haque.
      Malnutrition in children, defined as a child who is more than 2 standard deviations below the norm for height- or weight-for-age, is a pervasive, population-wide problem in low- and middle-income countries. Malnutrition is associated with increased infant mortality and delayed neurocognitive development. A recent pooled analysis of more than 30 longitudinal cohort studies demonstrated that the conditions mothers lived in during pregnancy, and their access to adequate nutrition, was a major factor in the subsequent growth and health of their children. We review here this analysis and the hypothesis that interventions to address childhood malnutrition need to start before birth and continue throughout the critical first 1,000 days of life.
    DOI:  https://doi.org/10.4269/ajtmh.24-0012
  11. J Cell Sci. 2024 Jun 01. pii: jcs261250. [Epub ahead of print]137(11):
    Histone acylation at a glance.
    Saikat Bhattacharya, Benjamin P Tu.
      An important mechanism of gene expression regulation is the epigenetic modification of histones. The cofactors and substrates for these modifications are often intermediary metabolites, and it is becoming increasingly clear that the metabolic and nutritional state of cells can influence these marks. These connections between the balance of metabolites, histone modifications and downstream transcriptional changes comprise a metabolic signaling program that can enable cells to adapt to changes in nutrient availability. Beyond acetylation, there is evidence now that histones can be modified by other acyl groups. In this Cell Science at a Glance article and the accompanying poster, we focus on these histone acylation modifications and provide an overview of the players that govern these acylations and their connections with metabolism.
    Keywords:  Acetylation; Acylation; Chromatin; Epigenetics; Histone modification; Metabolism
    DOI:  https://doi.org/10.1242/jcs.261250
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