Poster Presentation Multi-Omics Conference 2024

AP-1-linked chromatin opening hijacks developmental programming in aging by destabilizing early-life gene regulatory elements (#142)

Marina Naval-Sanchez 1 , Ralph Patrick 1 , Nikita Deshpande 1 2 , Yifei Huang 1 , Jingyu Zhang 1 , Xiaoli Chen 1 , Ying Yang 1 , Kanupriya Tiwary 1 , Mohammadhossein Esmaeili 1 , Minh Tran 1 , Amin R Mohammed 1 , Binxu Wang 1 , Di Xia 3 , Jun Ma 3 , Jacqueline Bayliss 4 , Kahlia Wong 5 , Michael L Hun 5 , Xuan Sun 6 7 , Benjamin Cao 6 7 , Denny L Cottle 5 , Tara Caterall 8 , Hila Barzilia-Tutsch 7 9 , Robin-Lee Troskie 10 , Zhian Chen 11 , Andrea F. Wise 12 , Sheetal Saini 12 , Ye Mon Soe 11 , Snehlata Kumari 11 , Matthew J Sweet 1 13 , Helen E Thomas 8 , Ian M Smyth 5 , Anne L Fletcher 7 14 , Konstantin Knoblich 7 14 , Mathew J Watt 4 , Majid Alhomrani 1 15 16 , Walaa Alsanie 15 16 , Kylie M Quinn 17 , Tobias D Merson 7 18 , Ann P Chidgey 5 , Sharon D Ricardo 12 , Di Yu 10 19 , Thierry Jardé 5 20 21 , Seth W Cheetham 10 , Christophe Marcelle 9 , Susan K Nilsson 6 7 , Quan Nguyen 1 22 , Melanie D White 1 22 , Christian M Nefzger 1 5 20 22
  1. Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, QLD, Australia
  2. WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia
  3. Genome Innovation Hub, The University of Queensland, St Lucia 4072, QLD, Australia
  4. Department of Anatomy and Physiology, Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Parkville 3010, VIC, Australia
  5. Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia
  6. Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organization, Melbourne, VIC, Australia
  7. Australian Regenerative Medicine Institute, Monash University, Clayton 3800, VIC, Australia
  8. St Vincent’s Institute of Medical Research, Fitzroy 3065, VIC, Australia
  9. Institut NeuroMyoGène, University Claude Bernard Lyon 1, Lyon 69008, France
  10. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia 4072, QLD, Australia
  11. Fraser Institute, Faculty of Medicine, The University of Queensland, Brisbane 4102, QLD, Australia
  12. Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia
  13. Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
  14. Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia
  15. Centre of Biomedical Sciences Research, Deanship of Scientific Research, Taif University, Taif, Saudi Arabia
  16. Department of Clinical Laboratories Sciences, Faculty of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
  17. School of Health and Biomedical Sciences, RMIT University, Bundoora 3083, VIC, Australia
  18. National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA
  19. Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane 4102, QLD, Australia
  20. Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia
  21. Cancer Program, Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, VIC, Australia
  22. School of Biomedical Sciences, The University of Queensland, St Lucia 4072, QLD, Australia

Whether there is a mechanistic connection between aging and developmental processes remains largely unexplored. Here, we report deep profiling of age-related chromatin remodeling and transcriptional changes in 22 murine cell types, analysed alongside public accessibility and transcriptional datasets for early organismal maturation in mouse and human. We unearth a transcription factor binding site (TFBS) code common to both processes, with early-life candidate cis-regulatory elements (cCREs), enriched for cell type identity TFBS, progressively losing accessibility during maturation and aging. Conversely, cCREs gaining accessibility throughout life have lower abundance of cell identity TFBS and are engaged through elevated AP-1 levels. Our data shows that AP-1-linked chromatin opening exposes competing TFBS for co-factors initially bound at early-life/developmental cCREs. According to our model, TF redistribution in synergy with mild downregulation of cell identity TFs drives accessibility loss of early-life cCREs, which alters the expression of developmental and metabolic genes. Such remodeling can be triggered by elevating AP-1 directly or indirectly (e.g. metabolic stress or via an age-increased serum factor), or by depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening commonly drives organismal maturation processes by disrupting cell identity TFBS rich cCREs and that persistence in aging hijacks this mechanism, offering a connection between development and molecular remodeling in aging. The resulting predictable transcription factor network changes may drive many aging phenotypes.