A single tRNA or rRNA can be cleaved at different sites, generating small RNAs with distinct functions depending on where the cuts are made. That fragmentation pattern is itself a regulatory layer beyond abundance — the "RNA fragmentome". With @tongzhoulab, we built qMAP, a tool to read this hidden information across development, disease & aging — for both mechanistic discovery and translational applications.

After years of crystallization, now in @NatureBiotech, @ZernickaGoetz and I discuss the evolutionary origins of multicellularity and how physical constraints inevitably drive cellular self-organization. Harnessing these rules may help us better understand and engineer life – Build to understand. rdcu.be/flTKa

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. xitter.cf/qichen_lab/status/2013…

1/5 It took us some time to connect the dots...now in @embojournal 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…

Our toolchain developed over the years to explore the expanding small RNA universe: PANDORA-seq (see the once invisible) nature.com/articles/s41556-0… nature.com/articles/s41596-0… SPORTS (comprehensive annotation) sciencedirect.com/science/ar… FUSION (robust comparison) academic.oup.com/bioinformat… qMAP (read the fragmentome) link.springer.com/article/10… Along with: Our thoughts on exploring the expanding universe of small RNAs with new tools: nature.com/articles/s41556-0… & Our reflections on small RNA origins & their functions beyond RNAi (aptamer-like) cell.com/trends/biochemical-… jbc.org/article/S0021-9258(2… cell.com/molecular-cell/full… cell.com/trends/biochemical-…

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.

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).

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.

Perhaps our boldest hypothesis… we propose a model for RNA Structural Memory propagation @NatureCellBio, 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