Christian Nefzger

Ralph Patrick is looking for dosage-sensitive transcription factors that may impact ageing #ASSCR2025 doi.org/10.1016/j.cm...

Could you add me too :)

Thanks for sharing the paper! Yes, we think AP-1 (with co-factors like Stat3) drives aging phenotypes like inflammaging. Various stimuli such as interleukins but also age-increased plasma factors like TGF-β (e.g. via tinyurl.com/4sdps2ty) can spike AP-1 activity (see Fig 6) & drive chromatin opening

bsky.app/profile/nefz...
Dear Jalees, thanks for promoting our recent study :)

🙏 Chris! I LOVE your own work in the AP-1 space 💛

Dear Michael, apologies for missing this earlier. Fascinating linkages in fly aging in your study: inflammation possibly preceding Smurf transition, Smurf genes associated with immune/stress responses & downregulation of PRC2 components, among other findings. Always happy to chat - feel free to DM 😊

🙋🏼‍♂️

Dear William, could you possibly add me. Thanks

Hi Patrick, if possible, could you add me to the list. Thanks

Dear Çağrı, could you possibly add me to the pack?

Really intriguing model of AP-1 driven aging.

@anshulkundaje.bsky.social @suragnair.bsky.social - thinking of your AP1-related results in the ChromBPNet paper here...

Dear Oliver, could you possibly add me to this pack?

Dear Angelo, could you possibly add me to the starter pack?

Dear Tatiana, could you add me to the Geroscience starter pack? Many thanks :)

Could you please add me to this one :)

Could you please add me to the starter pack too :) Thanks heaps

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

9/9 🧵 In aging, this mechanism is hijacked by continued AP-1-driven chromatin opening, induced by stress and inflammation, further diminishing the activity of developmental gene regulatory elements which may underpin many of the predictable phenotypes linked to aging.

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.