Perhaps the most puzzling part:
We see a paradox: the rsRNA length shift is progressive⏳yet the global RNA profile shows an "Aging Cliff"📉.
Cliff or Progression? Maybe the gradual shift is the forerunner—accumulating silently until it triggers the cliff.
bsky.app/profile/qich...
A molecular "aging clock" has been identified in human sperm RNA, showing progressive changes with age that may influence offspring health and metabolism. doi.org/hbkmvf
Fascinating research! Qi Chen and colleagues have identified a potential "aging cliff" in sperm RNA (rsRNA) that is associated with the increased health risks for the next generation that accompany advancing paternal age. Read on uofuhealth.utah.edu/newsroom/new...
What underlies the impact of sperm aging on fertility and offspring health?
small ncRNA profiling by Kenneth Aston, Tong Zhou, @qichen-lab.bsky.social and colleagues reveals a drastic shift in RNA complements able to affect recipient cell metabolism
link.springer.com/article/10.1...
Perhaps the most puzzling part:
We see a paradox: the rsRNA length shift is progressive⏳yet the global RNA profile shows an "Aging Cliff"📉.
Cliff or Progression? Maybe the gradual shift is the forerunner—accumulating silently until it triggers the cliff.
bsky.app/profile/qich...
5/5 Connecting mouse and human sperm data to uncover this conserved rsRNA length shift has been a privilege. Made possible by unique resources at @uuhsresearch.bsky.social
Huge thanks to the trainees & collaborators who made this happen! @jianchengyu.bsky.social
@cai000chen.bsky.social
4/5 Crucially, beyond mouse data, we validated the sperm-head-specific rsRNA length shift signal in two independent human cohorts (longitudinal & cross-sectional).
This suggests an evolutionarily conserved feature, which may stem from shared (enzymatic) mechanisms during aging.
3/5 Perhaps the most surprising discovery: we see an age-dependent "Length Shift" in rsRNAs, exclusively found in sperm heads.
Specifically, longer fragments accumulate while shorter ones decrease with age—a sign of altered RNA cleavage/processing efficiency (e.g., enzymatic).
2/5 The first revelation: In mice, PANDORA-seq uncovers a sharp "Aging Cliff"📉in sperm RNA profiles at mid-life—a non-linear shift distinct from chronological age.
Crucially, this cliff signal (genomic & mitochondrial tsRNAs/rsRNAs) is invisible to traditional small RNA-seq.
1/5 It took us some time to connect the dots...now in @embojournal.org we use PANDORA-seq to start decoding the 'sperm RNA code of aging'
We find a conserved rsRNA length shift that reflects aging in both mouse & human sperm, and an 'aging cliff' at mid-life🧵
link.springer.com/article/10.1...
A road trip to Monument Valley and the wonders of the west, as an anniversary of lab’s 10th year operation…look forward to the journey ahead…
Glad to see this thoughtful piece in @quantamagazine.bsky.social on paternal epigenetic inheritance and the emerging 'Sperm RNA Code', featuring many active colleagues in the field.
It’s a reminder that our actions may echo in the next generation(s) & there are immense unknowns to explore...
1/ Excited to share our new study with @brumbaugh-lab.bsky.social, out in @natbiotech.nature.com! P-bodies selectively sequester RNAs encoding cell fate regulators, often from the preceding developmental stage. Releasing these RNAs can drive changes in cell identity. 🧵 www.nature.com/articles/s41...
After developing PANDORA-seq to reveal hidden small RNAs (e.g., tsRNA, rsRNA) and SPORTS to annotate them, we now expand our toolchain with Tong Zhou lab: introducing FUSION, a tool that robustly interprets small RNA changes even in small or 1-on-1 datasets.
academic.oup.com/bioinformati...
Proud to work with a brave team @cai000chen.bsky.social @jianchengyu.bsky.social Xudong Zhang & Tong Zhou—thinking fearlessly to bring this piece together.
In a time of uncertainty, may this idea be a seed for spring… We’ll see what evidence we and the community can bring, to confirm or refute…
Beyond inheritance, the model may also apply to cancer & neurodegeneration, where abnormal RNA structures could shape pathological cell states.
Perhaps misfolded RNAs — not just amyloid proteins — are the central structural entity driving disease.
Why the memory fades eventually - as often seen in epigenetic inheritance:
Two potential exits:
Active reset: when conditions normalize, condensates dissolve, RBPs shift, RNA refolds.
Passive fade: cells with stress-memory may grow slower, and are outcompeted over generations.
Memory propagation in cells — and across generations:
Newly folded RNAs bind stress-linked RBPs to assemble new condensates, passed on during cell division.
Even daughter cells never facing the original stress can inherit the RNA structural memory – and its stress-adapted traits.
The heart of the hypothesis: copying RNA shape.
Some RNAs can act as both template & catalyst, guiding new RNAs with the same sequence to fold the same way.
RNA alone is unstable, but RBPs stabilize the template, & condensates boost RNA–RNA interactions—as a microreaction chamber
The model starts with RNA folding energy & a multistable landscape.
Under stress, RNA can adopt a new shape—and if RNA-binding proteins “lock” it in, that shape becomes a molecular memory of the stress.
Think Waddington’s epigenetic landscape—but for RNA folding energy valleys.
Perhaps our boldest hypothesis… we propose a model for RNA Structural Memory propagation in @natcellbio.nature.com where RNA conformation is reshaped by stress, locked by RBPs, copied prion-like in condensates & passed across generations—all without altering DNA
rdcu.be/eBwPJ
Our 🌷 May 🌷 issue is online with a broad range of article topics and formats!
In their Opinion article (on the cover, too!), @qichen-lab.bsky.social and colleagues describe the interactions between small ncRNAs and Toll-like receptors.
Find the issue here: www.cell.com/trends/bioch...
Very glad to see our Sequential Activation Hypothesis highlighted on the cover @cp-trendsbiochem.bsky.social , linking small RNA-TLR interactions to autoimmune disease mechanisms.
#NewNProt for #genomewide characterization of a diverse set of #smallnoncodingRNAs in cells and tissues
We put together a step-by-step protocols for PANDORA-seq, now available in Nature Protocols @natprot.bsky.social , including the sample preparation for sperm, sperm heads; and the analyzing software SPORTS optimized for various types of small RNAs including tsRNAs, rsRNAs, and miRNAs. rdcu.be/egk1Z
Proud of @jianchengyu.bsky.social and the team for thinking fearlessly to put the ideas together!
This idea is driven by advanced sncRNA sequencing (e.g. PANDORA-seq), uncovering an expanding universe of tsRNA/rsRNA/ysRNA & more www.nature.com/articles/s41...
These sncRNAs go beyond RNAi, adopting aptamer-like roles by binding TLR7/8 to shape immune responses
www.jbc.org/article/S002...
TLR7/8 aren’t just triggered by viral RNAs, they can be potentially activated by a range of RNA resources: cell stress/death, RNA therapies, microbiome, and even dietary RNAs.
Uncovering these diverse triggers may pave new paths for preventing/treating autoimmune diseases.
How can abnormal small RNA biogenesis spark autoimmune disease? Our opinion @cp-trendsbiochem.bsky.social discuss a novel two-stage activation hypothesis that may explain why autoimmunity hits women harder, via small RNA-TLR7/8 interactions & augmented by autoantibodies.
www.cell.com/trends/bioch...
go.bsky.app/QkSL6S5
