The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening

Ralph Patrick; Marina Naval-Sanchez; Nikita Deshpande; Yifei Huang; Jingyu Zhang; Xiaoli Chen; Ying Yang; Kanupriya Tiwari; Mohammadhossein Esmaeili; Minh Tran; Amin R Mohamed; Binxu Wang; Di Xia; Jun Ma; Jacqueline Bayliss; Kahlia Wong; Michael L Hun; Xuan Sun; Benjamin Cao; Denny L Cottle; Tara Catterall; Hila Barzilai-Tutsch; Robin-Lee Troskie; Zhian Chen; Andrea F Wise; Sheetal Saini; Ye Mon Soe; Snehlata Kumari; Matthew J Sweet; Helen E Thomas; Ian M Smyth; Anne L Fletcher; Konstantin Knoblich; Matthew J Watt; Majid Alhomrani; Walaa Alsanie; Kylie M Quinn; Tobias D Merson; Ann P Chidgey; Sharon D Ricardo; Di Yu; Thierry Jardé; Seth W Cheetham; Christophe Marcelle; Susan K Nilsson; Quan Nguyen; Melanie D White; Christian M Nefzger

doi:10.1016/j.cmet.2024.06.006

The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening

Cell Metab. 2024 Aug 6;36(8):1858-1881.e23. doi: 10.1016/j.cmet.2024.06.006. Epub 2024 Jul 2.

Authors

Ralph Patrick¹, Marina Naval-Sanchez¹, Nikita Deshpande², Yifei Huang¹, Jingyu Zhang¹, Xiaoli Chen¹, Ying Yang¹, Kanupriya Tiwari¹, Mohammadhossein Esmaeili¹, Minh Tran¹, Amin R Mohamed¹, Binxu Wang¹, Di Xia³, Jun Ma³, Jacqueline Bayliss⁴, Kahlia Wong⁵, Michael L Hun⁵, Xuan Sun⁶, Benjamin Cao⁶, Denny L Cottle⁵, Tara Catterall⁷, Hila Barzilai-Tutsch⁸, Robin-Lee Troskie⁹, Zhian Chen¹⁰, Andrea F Wise¹¹, Sheetal Saini¹¹, Ye Mon Soe¹⁰, Snehlata Kumari¹⁰, Matthew J Sweet¹², Helen E Thomas⁷, Ian M Smyth⁵, Anne L Fletcher¹³, Konstantin Knoblich¹³, Matthew J Watt⁴, Majid Alhomrani¹⁴, Walaa Alsanie¹⁴, Kylie M Quinn¹⁵, Tobias D Merson¹⁶, Ann P Chidgey⁵, Sharon D Ricardo¹¹, Di Yu¹⁷, Thierry Jardé¹⁸, Seth W Cheetham⁹, Christophe Marcelle⁸, Susan K Nilsson⁶, Quan Nguyen¹⁹, Melanie D White¹⁹, Christian M Nefzger²⁰

Affiliations

¹ Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia.
² Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia; WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
³ Genome Innovation Hub, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia.
⁴ Department of Anatomy and Physiology, Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia.
⁵ Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
⁶ Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organization, Melbourne, VIC, Australia; Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
⁷ St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
⁸ Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia; Institut NeuroMyoGène, University Claude Bernard Lyon 1, 69008 Lyon, France.
⁹ Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia.
¹⁰ Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia.
¹¹ Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
¹² Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia.
¹³ Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
¹⁴ Department of Clinical Laboratories Sciences, Faculty of Applied Medical Sciences, Taif University, Taif, Saudi Arabia; Research Centre for Health Sciences, Taif University, Taif, Saudi Arabia.
¹⁵ Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia.
¹⁶ Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia; National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
¹⁷ Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia; Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia.
¹⁸ Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Cancer Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Department of Surgery, Cabrini Monash University, Malvern, VIC 3144, Australia.
¹⁹ Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia; School of Biomedical Sciences, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia.
²⁰ Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia. Electronic address: [email protected].

PMID: 38959897
DOI: 10.1016/j.cmet.2024.06.006

Abstract

A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.

Keywords: AP-1; CTCF; aging; cell identity; chromatin; development; maturation; polycomb repressive complex 2; redistribution; transcription factors.

MeSH terms

Aging* / genetics
Aging* / metabolism
Animals
Binding Sites
Chromatin* / metabolism
Humans
Mice
Mice, Inbred C57BL
Transcription Factor AP-1* / metabolism

Substances

Transcription Factor AP-1
Chromatin