Transcriptomes of human primary skin fibroblasts of healthy individuals reveal age‐associated mRNAs and long noncoding RNAs

Changes in the transcriptomes of human tissues with advancing age are poorly cataloged. Here, we sought to identify the coding and long noncoding RNAs present in cultured primary skin fibroblasts collected from 82 healthy individuals across a wide age spectrum (22-89 years old) who participated in the GESTALT (Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing) study of the National Institute on Aging, NIH. Using high-throughput RNA sequencing and a linear regression model, we identified 1437 coding RNAs (mRNAs) and 1177 linear and circular long noncoding (lncRNAs) that were differentially abundant as a function of age. Gene set enrichment analysis (GSEA) revealed select transcription factors implicated in coordinating the transcription of subsets of differentially abundant mRNAs, while long noncoding RNA enrichment analysis (LncSEA) identified RNA-binding proteins predicted to participate in the age-associated lncRNA profiles. In summary, we report age-associated changes in the global transcriptome, coding and noncoding, from healthy human skin fibroblasts and propose that these transcripts may serve as biomarkers and therapeutic targets in aging skin.

[1]  L. Ferrucci,et al.  Skin Barrier Function and Cognition Among Older Adults. , 2023, The Journal of investigative dermatology.

[2]  A. Moore,et al.  DNA methylation signatures reveal that distinct combinations of transcription factors specify human immune cell epigenetic identity. , 2022, Immunity.

[3]  M. Gorospe,et al.  Integrated lncRNA function upon genomic and epigenomic regulation. , 2022, Molecular cell.

[4]  Amogh H Kashyap,et al.  Proteomes of primary skin fibroblasts from healthy individuals reveal altered cell responses across the life span , 2022, Aging cell.

[5]  M. Ristow,et al.  Evolutionarily conserved transcription factors as regulators of longevity and targets for geroprotection. , 2022, Physiological reviews.

[6]  Ludi Zhang,et al.  Roles of extracellular vesicles in the aging microenvironment and age‐related diseases , 2021, Journal of extracellular vesicles.

[7]  Audrey M. Michel,et al.  HMGB1 coordinates SASP‐related chromatin folding and RNA homeostasis on the path to senescence , 2021, Molecular systems biology.

[8]  M. van Dijk,et al.  Knockdown of Splicing Complex Protein PCBP2 Reduces Extravillous Trophoblast Differentiation Through Transcript Switching , 2021, Frontiers in Cell and Developmental Biology.

[9]  Yu Yongji,et al.  hsa_circ_0071106 can be used as a diagnostic marker for type 2 diabetes , 2021, International journal of medical sciences.

[10]  Olga Anczuków,et al.  Splicing alterations in healthy aging and disease , 2021, Wiley interdisciplinary reviews. RNA.

[11]  M. Gorospe,et al.  AUF1 ligand circPCNX reduces cell proliferation by competing with p21 mRNA to increase p21 production. , 2021, Nucleic acids research.

[12]  S. Lemon,et al.  Interferon regulatory factor 1 (IRF1) and anti-pathogen innate immune responses , 2021, PLoS pathogens.

[13]  J. I. Izpisúa Belmonte,et al.  A Single-Cell Transcriptomic Atlas of Human Skin Aging. , 2020, Developmental cell.

[14]  V. Jaks,et al.  Primary Ciliary Signaling in the Skin—Contribution to Wound Healing and Scarring , 2020, Frontiers in Cell and Developmental Biology.

[15]  Jian Zhang,et al.  LncSEA: a platform for long non-coding RNA related sets and enrichment analysis , 2020, Nucleic Acids Res..

[16]  K. Ikegami,et al.  Current understandings of the relationship between extracellular vesicles and cilia. , 2020, Journal of biochemistry.

[17]  S. Frisch,et al.  Type I interferons and related pathways in cell senescence , 2020, Aging cell.

[18]  T. Quan,et al.  Alterations in extracellular matrix composition during aging and photoaging of the skin , 2020, Matrix biology plus.

[19]  H. You,et al.  LncRNA SOCS2-AS1 inhibits progression and metastasis of colorectal cancer through stabilizing SOCS2 and sponging miR-1264 , 2020, Aging.

[20]  Bill B. Chen,et al.  The RNFT2/IL3Rα axis regulates IL3 signaling and innate immunity. , 2020, JCI insight.

[21]  L. Bonewald,et al.  Fibroblast growth factor 9 (FGF9) inhibits myogenic differentiation of C2C12 and human muscle cells , 2019, Cell cycle.

[22]  Kotb Abdelmohsen,et al.  Transcriptome signature of cellular senescence. , 2019, Nucleic acids research.

[23]  P. Mitteroecker,et al.  Facial aging trajectories: A common shape pattern in male and female faces is disrupted after menopause , 2019, American journal of physical anthropology.

[24]  O. Kepp,et al.  Targeting GATA transcription factors – a novel strategy for anti-aging interventions? , 2019, Microbial cell.

[25]  A. Moore,et al.  Plasma proteomic signature of age in healthy humans , 2018, Aging cell.

[26]  P. Humbert,et al.  Male versus female skin: What dermatologists and cosmeticians should know , 2018, International journal of women's dermatology.

[27]  E. Duan,et al.  Fighting against Skin Aging , 2018, Cell transplantation.

[28]  M. Takasugi.  Emerging roles of extracellular vesicles in cellular senescence and aging , 2018, Aging cell.

[29]  Gerry Melino,et al.  Zinc-finger proteins in health and disease , 2017, Cell Death Discovery.

[30]  Li Yang,et al.  Coordinated circRNA Biogenesis and Function with NF90/NF110 in Viral Infection. , 2017, Molecular cell.

[31]  K. Kaestner,et al.  Fox transcription factors: from development to disease , 2016, Development.

[32]  Michael L. Gatza,et al.  Proteogenomics connects somatic mutations to signaling in breast cancer , 2016, Nature.

[33]  P. Mordant,et al.  FGF9 and FGF18 in idiopathic pulmonary fibrosis promote survival and migration and inhibit myofibroblast differentiation of human lung fibroblasts in vitro. , 2016, American journal of physiology. Lung cellular and molecular physiology.

[34]  Dawood B. Dudekula,et al.  CircInteractome: A web tool for exploring circular RNAs and their interacting proteins and microRNAs , 2016, RNA biology.

[35]  G. Melino,et al.  DNA repair and aging: the impact of the p53 family , 2015, Aging.

[36]  Anne-Marie Alleaume,et al.  FASTKD2 is an RNA-binding protein required for mitochondrial RNA processing and translation , 2015, RNA.

[37]  N. Grabe,et al.  Characterization of Skin Aging-Associated Secreted Proteins (SAASP) Produced by Dermal Fibroblasts Isolated from Intrinsically Aged Human Skin. , 2015, The Journal of investigative dermatology.

[38]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[39]  M. Gorospe,et al.  Long noncoding RNAs (lncRNAs) and the molecular hallmarks of aging , 2014, Aging.

[40]  Ling-Ling Chen,et al.  Complementary Sequence-Mediated Exon Circularization , 2014, Cell.

[41]  L. Ferrucci,et al.  “IDEAL” Aging Is Associated with Lower Resting Metabolic Rate: The Baltimore Longitudinal Study of Aging , 2014, Journal of the American Geriatrics Society.

[42]  Wei Shi,et al.  featureCounts: an efficient general purpose program for assigning sequence reads to genomic features , 2013, Bioinform..

[43]  Julian König,et al.  Direct Competition between hnRNP C and U2AF65 Protects the Transcriptome from the Exonization of Alu Elements , 2013, Cell.

[44]  J. Massagué.  TGFβ signalling in context , 2012, Nature Reviews Molecular Cell Biology.

[45]  N. Schaum,et al.  p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes , 2011, The Journal of cell biology.

[46]  S. Park,et al.  Candidate gene polymorphisms for diabetes mellitus, cardiovascular disease and cancer are associated with longevity in Koreans , 2009, Experimental & Molecular Medicine.

[47]  Davis J. McCarthy,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[48]  M. Morasso,et al.  Role of homeobox genes in the patterning, specification, and differentiation of ectodermal appendages in mammals , 2008, Journal of cellular physiology.

[49]  H. Aguilaniu,et al.  PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans , 2007, Nature.

[50]  C. Zouboulis,et al.  Characteristics and Pathomechanisms of Endogenously Aged Skin , 2007, Dermatology.

[51]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[52]  S. Brody,et al.  Role of f-box factor foxj1 in differentiation of ciliated airway epithelial cells. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[53]  Cynthia Kenyon,et al.  Regulation of Aging and Age-Related Disease by DAF-16 and Heat-Shock Factor , 2003, Science.

[54]  Markus Affolter,et al.  Structural basis of BMP signalling inhibition by the cystine knot protein Noggin , 2002, Nature.

[55]  James Varani,et al.  Mechanisms of photoaging and chronological skin aging. , 2002, Archives of dermatology.

[56]  R Grosschedl,et al.  DNA-binding properties of the HMG domain of the lymphoid-specific transcriptional regulator LEF-1. , 1991, Genes & development.

[57]  J. Studd,et al.  Sex hormones and skin collagen content in postmenopausal women. , 1983, British medical journal.

[58]  M. Gorospe,et al.  Long noncoding RNAs in diseases of aging. , 2016, Biochimica et biophysica acta.

[59]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[60]  I. Um,et al.  Relationship between differentially expressed mRNA and mRNA-protein correlations in a xenograft model system , 2015, Scientific Reports.