Júlia Bonjoch

SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging Tran et al. determined that the protein deacetylase SIRT7 is degraded during senescence by the E3 ligase TRIP12. SIRT7 binds to NUCKS1 and, upon SIRT7 loss, NUCKS1 is acetylated and recruited onto chromatin, where it regulates genes involved in senescence and aging. This SIRT7-NUCKS1 relationship was also demonstrated during liver aging.

SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging

Thanks a lot, Maria!

Thanks for all the support and discussions, Sara!

20/ Biostatistics/Bioinformatics IRB facility scientists from @irbbarcelona.org + best colleagues and friends Paloma Solá @guiomarsolanas.bsky.social @circatom.bsky.social @aznarbenitahlab.bsky.social

19/ Thanks for making it until the end! Last but not least, most special thanks go to all the people who helped this project finally make it to a written article, including our mechanobiology expert collaborators @sarawickstrom.bsky.social @katemiro.bsky.social +

18/ During ageing, following YAP activation, BMAL1-YAP complex is directed to enhancers of inflammation genes, many of which are regulated by p65. All this leads to an increase in expression of these genes, contributing to the transcriptional rewiring of epid cells during ageing.

17/ Finally, based on all the above-mentioned results, we propose the following molecular mechanism:

In adult epidermis, during homeostatic conditions, BMAL1 and YAP coordinately bind to enhancers of identity and maintenance genes.➕

16/ Now, a more detailed p65 genomic occupancy analysis revealed the presence of p65 in promoters and TSSs of up-regulated inflammation-related genes, some of which present BMAL1-YAP bound enhancers.

15/ We consistently found p65-NF-kB binding sites enriched in active enhancers bound by BMAL1 and YAP in aged epidermis.

Actually, we have already shown in a previous study that p65 plays a key role in controlling the expression of inflammation genes during epidermal ageing!👀

14/ What’s more, some of the up-regulated inflammation-related genes that were BMAL1 or YAP targets in adult epidermis, gain BMAL1-YAP binding in their enhancers with age.

13/ What about BMAL1-YAP complex? Indeed, when we compare both TFs ChIP-seq data, we observe a stat significant genomic overlap between the two TFs.
+ Notably, during ageing, this happens in active enhancers of inflammation genes, some of which expression is up-regulated.

12/ These suggest that, in addition to mechanical changes of the skin, pro-inflammatory cues act as a second signalling layer that leads to ageing-associated YAP activation. 👯

11/ Yes! We show that a non-canonical YAP activation through phosphorylation of Tyr357 is increased in the aged epidermis, and that this activation is reduced upon anti-inflammatory treatment with anti-IL17 blocking antibodies.

10/ Using a Col14KO mouse to model skin ageing mechanics, we unveiled that YAP activation through mechanotransduction signalling alone is not enough to recapitulate YAP aged binding to inflammation genes.

So, are there other triggers that can boost YAP activation during ageing?

9/ Could YAP activation be involved in BMAL1 genomic location rewiring to inflammation-related genes we observe during ageing?

To tackle that, we first needed to gain a little insight into how YAP activation happens during ageing. ⤵️

8/ However, during ageing, YAP gains binding to inflammation-related genes, similar to what we see for BMAL1. In fact, BMAL1 binding sites are enriched exclusively in aged YAP peaks located in active enhancers.😮

7/ In vivo ChIP-seq analysis of YAP in the epidermis confirmed its well-known role as a mechanotransduction TF, as its genomic occupancy is enriched in mechanics- and Hippo-related genes.🦛

6/ Other groups have underscored that changes in tissue mechanics occur during ageing. In the IFE, we observed an increased stiffness of the BM during ageing, and this correlates with an increased proportion of epidermal cells positive for the Hippo-dependent active YAP.❗️

5/ TF motif enrichment analysis of BMAL1 peaks in active enhancers revealed TEAD binding sites.

PLA assay on skin sections shows BMAL1-YAP interactions in the nucleus of epidermal cells, suggesting a possible BMAL1 and YAP functional interaction in the epidermis chromatin.🧐

4/ In addition, we also see that BMAL1 binding is not restricted to rhythmically expressed genes, supporting a non-canonical BMAL1 function as a transcription factor beyond its role in the circadian clock.😈

3/ In vivo ChIP-seq revealed BMAL1 binding to be enriched in inflammation genes in the aged epidermis, while during adulthood, this binding is more restricted to homeostatic genes.

Moreover, this binding occurs in enhancers, emphasising BMAL1 role in enhancer regulation.

2/ By performing a comprehensive analysis of DEGs throughout 24 hours in adult and aged murine epidermis, we reveal a list of more than 100 up-regulated genes during ageing associated with inflammation functions.

But who promotes such an expression program?

BMAL1 and YAP cooperate to hijack enhancers and promote inflammation in the aged epidermis Ageing is characterised by persistent low-grade inflammation that is linked to impaired tissue homeostasis and functionality. However, the molecular mechanisms driving age-associated inflammation rema...

Hi Bluesky community:)

Our new manuscript is now available as a preprint!⛅️
biorxiv.org/content/10.1...

1/ Here, we describe a novel BMAL1-YAP complex in epidermal cells, which is hijacked during ageing to control the expression of up-regulated inflammation genes through enhancer binding.🧵

BMAL1 and YAP cooperate to hijack enhancers and promote inflammation in the aged epidermis Ageing is characterised by persistent low-grade inflammation that is linked to impaired tissue homeostasis and functionality. However, the molecular mechanisms driving age-associated inflammation rema...

🌟 Excited to share that our latest preprint is now available! We’re one step closer to understanding the complex mechanisms behind ageing and inflammation.
👉 Read the preprint here: www.biorxiv.org/cgi/content/...
Thank you to everyone who supported and believed in this project along the way!

Circadian clock communication during homeostasis and ageing Nature Reviews Molecular Cell Biology - Communication between the circadian clocks of different cell and tissue types supports the daily rhythms of homeostatic processes that maintain bodily...

🧪 ✍️ Please check out our new review on intercellular and interorgan communication between circadian clocks ⏰🧬 out today in Nature Reviews Molecular Cell Biology 🎉
@natrevmcb.bsky.social
! Here is the SharedIt link for free access: rdcu.be/d5ppE