We introduce the "Stimulus-Induced Programming Hijacks Ontogeny" (SIPHON) model based on compelling evidence that chromatin & transcription factor network remodeling in aging reflects the predictable degrading effects of a mechanism initially driving organismal maturation
doi.org/10.1016/j.cm...

🙏 to Manuel Serrano for writing a preview for our study @ Cell Metabolism. A pattern emerges in chromatin aging: AP-1 steals the show dlvr.it/TBvzgR

Thanks to Longevity Technology for writing an article about our recent study:
"Master controller of aging and development uncovered.
New insights into transcription factors and chromatin remodeling reveal potential for improving age-related health outcomes. #innovation #aging "
t.co/a8Mxgowkbe

Thanks to EpiGenie for an article about our study: "Christian Nefzger's lab reveals how chromatin remodeling driven by the AP-1 pioneer transcription factor supports cell maturation. Beware o' the mechanism pirated during #aging to induce the appearance of age-related phenotypes!" bit.ly/3zOqBux

8/9 🧵 Our study indicates that AP-1–linked chromatin opening drives organismal maturation by disrupting the activity of cell identity TFBS-rich early-life REs, thereby progressively shutting down developmental processes to reprogram the transcriptome towards adult tissue function.

7/9 🧵 Such remodelling can be triggered by directly elevating AP-1 through overexpression or indirectly via metabolic stress or the age-increased systemic factor TGFβ. H3K27me3 depletion partially phenocopied AP-1 overexpression in support of a critical role of loss of epigenetic repression.

6/9 🧵 We show that redistribution of TFs to age-exposed AP-1-TFBS-rich REs, in synergy with mild down-regulation of cell identity TF expression drives accessibility loss of early-life REs and underpins age-altered gene expression

5/9 🧵 Early-life gene regulatory elements (REs) are engaged through cell type identity TFs and progressively loose accessibility during maturation & aging. Conversely REs gaining accessibility throughout life have fewer cell identity TFBS and rely on elevated activity of TF AP-1 for engagement.

4/9 🧵 By studying transcription factor binding site (TFBS) patterns in regions that open/close with age we found a common signature across cell types. Remarkably, by reanalyzing many previous data sets for organismal maturation (incl. human data spanning life-stages) we found the same TFBS pattern.

3/9 🧵 Multi-omic profiling of 22 mouse cell types (young vs aged) revealed robust connectivity between the age-altered chromatin accessibility landscape and transcriptional output. This included widespread modulation of developmental genes as part of cell type/lineage-specific accessibility changes.

2/9 🧵 Transcription factor (TF) networks regulate gene expression & cell function. To understand how they change across life, with a focus on aging, we studied chromatin accessibility & transcriptional changes during developmental maturation & aging across >45 mouse & human cell types.

Our recent study in Cell Metabolism provides compelling evidence that chromatin accessibility and transcription factor network remodeling in aging reflect the predictable degrading effects of a mechanism initially driving organismal maturation.
Link: doi.org/10.1016/j.cmet.2024.06.006
Thread 🧵👇1/9

8/10 🧵 Our study indicates that AP-1–linked chromatin opening drives organismal maturation by disrupting the activity of cell identity TFBS-rich early-life REs, thereby progressively shutting down developmental processes to reprogramming the transcriptome to adult tissue function.

7/10 🧵 Such remodelling can be triggered by directly elevating AP-1 through overexpression or indirectly via metabolic stress or the age-increased systemic factor TGFβ. H3K27me3 depletion partially phenocopied AP-1 overexpression in support of a critical role of loss of epigenetic repression.

6/10 🧵 We show that redistribution of TFs to age-exposed AP-1-TFBS-rich REs, in synergy with mild down-regulation of cell identity TF expression drives accessibility loss of early-life REs and underpins age-altered gene expression.

5/10 🧵 Early-life gene regulatory elements (REs) are engaged through cell type identity TFs and progressively loose accessibility during maturation & aging. Conversely REs gaining accessibility throughout life have fewer cell identity TFBS and rely on elevated activity of TF AP-1 for engagement.

4/10 🧵 By studying transcription factor binding site (TFBS) patterns in regions that open/close with age we found a common signature across cell types. Remarkably, by reanalyzing many previous data sets for organismal maturation (incl. human data spanning life-stages) we found the same TFBS pattern.

3/10 🧵 Multi-omic profiling of 22 mouse cell types (young vs aged) revealed robust connectivity between the age-altered chromatin accessibility landscape and transcriptional output. This included widespread modulation of developmental genes as part of cell type/lineage-specific accessibility changes

2/10 🧵 Transcription factor (TF) networks regulate gene expression & cell function. To understand how they change across life, with a focus on aging, we studied chromatin accessibility & transcriptional changes during developmental maturation & aging across >45 mouse & human cell types.