1. Chromosomes and Gene Expression
Download icon

miR-125-chinmo pathway regulates dietary restriction dependent enhancement of lifespan in Drosophila

  1. Manish Pandey
  2. Sakshi Bansal
  3. Sudipta Bar
  4. Amit Kumar Yadav
  5. Nicholas S Sokol
  6. Jason M Tennessen
  7. Pankaj Kapahi  Is a corresponding author
  8. Geetanjali Chawla  Is a corresponding author
  1. Regional Centre for Biotechnology, India
  2. Buck Institute for Research on Aging, United States
  3. Translational Health Science and Technology Institute, India
  4. Indiana University, United States
Research Article
  • Cited 0
  • Views 329
  • Annotations
Cite this article as: eLife 2021;10:e62621 doi: 10.7554/eLife.62621

Abstract

Dietary restriction (DR) extends healthy lifespan in diverse species. Age and nutrient-related changes in the abundance of microRNAs (miRNAs) and their processing factors have been linked to organismal longevity. However, the mechanisms by which they modulate lifespan and the tissue-specific role of miRNA-mediated networks in DR-dependent enhancement of lifespan remains largely unexplored. We show that two neuronally enriched and highly conserved microRNAs, miR-125 and let-7 mediate the DR response in Drosophila melanogaster. Functional characterization of miR-125 demonstrates its role in neurons while its target chinmo acts both in neurons and the fat body to modulate fat metabolism and longevity. Proteomic analysis revealed that Chinmo exerts its DR effects by regulating the expression of FATP, CG2017, CG9577, CG17554, CG5009, CG8778, CG9527, and FASN1. Our findings identify miR-125 as a conserved effector of the DR pathway and open the avenue for this small RNA molecule and its downstream effectors to be considered as potential drug candidates for the treatment of late-onset diseases and biomarkers for healthy aging in humans.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3, 4, 5, 6, 7, 8.Proteomics analysis data done in Figure 7 is also provided in Supplementary files 3 and 4 (Upregulated and downregulated processes).

Article and author information

Author details

  1. Manish Pandey

    RNA Biology Laboratory, Regional Centre for Biotechnology, Faridabad, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Sakshi Bansal

    RNA Biology Laboratory, Regional Centre for Biotechnology, Faridabad, India
    Competing interests
    The authors declare that no competing interests exist.
  3. Sudipta Bar

    Larry L. Hillblom Center for Integrative Studies of Aging, Buck Institute for Research on Aging, Novato, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Amit Kumar Yadav

    NCD, Translational Health Science and Technology Institute, Faridabad, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9445-8156
  5. Nicholas S Sokol

    Department of Biology, Indiana University, Bloomington, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jason M Tennessen

    Department of Biology, Indiana University, Bloomington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3527-5683
  7. Pankaj Kapahi

    Larry L. Hillblom Center for Integrative Studies of Aging, Buck Institute for Research on Aging, Novato, United States
    For correspondence
    Pkapahi@buckinstitute.org
    Competing interests
    The authors declare that no competing interests exist.
  8. Geetanjali Chawla

    RNA Biology Laboratory, Regional Centre for Biotechnology, Faridabad, India
    For correspondence
    gchawla@rcb.res.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0354-3716

Funding

DBT-Wellcome Trust India Alliance (IA/I(S)/17/1/503085)

  • Geetanjali Chawla

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Dario Riccardo Valenzano, Max Planck Institute for Biology of Ageing, Germany

Publication history

  1. Received: September 1, 2020
  2. Accepted: June 7, 2021
  3. Accepted Manuscript published: June 8, 2021 (version 1)

Copyright

© 2021, Pandey et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 329
    Page views
  • 50
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Christopher Duncan-Lewis et al.
    Research Article Updated

    RNA abundance is generally sensitive to perturbations in decay and synthesis rates, but crosstalk between RNA polymerase II transcription and cytoplasmic mRNA degradation often leads to compensatory changes in gene expression. Here, we reveal that widespread mRNA decay during early apoptosis represses RNAPII transcription, indicative of positive (rather than compensatory) feedback. This repression requires active cytoplasmic mRNA degradation, which leads to impaired recruitment of components of the transcription preinitiation complex to promoter DNA. Importin α/β-mediated nuclear import is critical for this feedback signaling, suggesting that proteins translocating between the cytoplasm and nucleus connect mRNA decay to transcription. We also show that an analogous pathway activated by viral nucleases similarly depends on nuclear protein import. Collectively, these data demonstrate that accelerated mRNA decay leads to the repression of mRNA transcription, thereby amplifying the shutdown of gene expression. This highlights a conserved gene regulatory mechanism by which cells respond to threats.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Amy R Strom et al.
    Research Article

    Chromatin, which consists of DNA and associated proteins, contains genetic information and is a mechanical component of the nucleus. Heterochromatic histone methylation controls nucleus and chromosome stiffness, but the contribution of heterochromatin protein HP1α (CBX5) is unknown. We used a novel HP1α auxin-inducible degron human cell line to rapidly degrade HP1α. Degradation did not alter transcription, local chromatin compaction, or histone methylation, but did decrease chromatin stiffness. Single-nucleus micromanipulation reveals that HP1α is essential to chromatin-based mechanics and maintains nuclear morphology, separate from histone methylation. Further experiments with dimerization-deficient HP1αI165E indicate that chromatin crosslinking via HP1α dimerization is critical, while polymer simulations demonstrate the importance of chromatin-chromatin crosslinkers in mechanics. In mitotic chromosomes, HP1α similarly bolsters stiffness while aiding in mitotic alignment and faithful segregation. HP1α is therefore a critical chromatin-crosslinking protein that provides mechanical strength to chromosomes and the nucleus throughout the cell cycle and supports cellular functions.