Cledi Cerda-Jara

🚨 In our new preprint, and using an organoids model, we show that miRNAs act within a precise temporal window to control cell fate decisions in the human forebrain.🧠 biorxiv.org/content/10.648…

The work describes a longitudinal study of miRNA expression dynamics and functions during early human brain development. A team effort lead by @EmmeneggerLisa @N_Rajewsky @AgaRybak, me and many more! Check it out! biorxiv.org/content/10.648…

🚨 In our new preprint, and using an organoids model, we show that miRNAs act within a precise temporal window to control cell fate decisions in the human forebrain.🧠 biorxiv.org/content/10.648…

Excited to share the published version of our work @Nature! We revealed the mechanism + structural basis of microRNA degradation, and showed how ZSWIM8 defines a novel class of Cullin–RING E3 ligases + targets an asymmetric substrate as a dimer + uses RNAs in recognition. [1/2]

A new mechanism for “RNA memory”! 😱 Thrilled to share another crazy paper from the lab (can’t believe we posted 2 in 2 days!), summarizing >10 years of research: Work on transgenerational inheritance of small RNAs in the powerful model organism C. elegans changed how we think about what’s possible in inheritance and evolution, because it allows the most heretical thing: inheritance of parental responses to the environment! However, it’s still unclear whether RNAs are inherited across generations in other animals, largely because the RNA-dependent RNA polymerases that amplify heritable small RNAs and prevent their dilution in C. elegans are not conserved in mammals. In this new work, an amazing collaboration with the Rink and Wurtzel labs, we show that planarians establish long-lasting and heritable small RNA–based gene regulatory states despite lacking canonical RNA-dependent RNA polymerases and nuclear RNAi machinery (that are required in C. elegans). You might say “they are both worms…” BUT planarians are evolutionarily very distant from C. elegans (flatworms vs. roundworms, diverged more than 500 million years ago), making this particularly surprising. These are totally different animals. We find that ingestion of double-stranded RNA induces sequence-specific silencing that persists for months and survives repeated cycles of whole-body regeneration. Even more strikingly, RNAi can be transferred between animals, echoing James V. McConnell’s controversial “RNA memory” experiments from the 1970s (his lab was targeted by the Unabomber terrorist Ted Kaczynski, who sent McConnell a bomb. This and other controversies ended this line of experiments…) Mechanistically, we find that the response transitions from a transient systemic dsRNA-triggered phase to a stable, cell-autonomous post-transcriptional “memory phase” maintained by antisense small RNAs. Using a new luminescence reporter (transgenesis is currently impossible in planarians), we show that silencing spreads along the targeted gene and identify a weird type of planarian small RNAs with untemplated polyA tails. RNAi inheritance without canonical RdRPs establishes planarians as a powerful system for studying RNA-based regulatory inheritance beyond C. elegans and raises the possibility that RNA-mediated inheritance may be more broadly conserved in animals, potentially even in mammals. Here’s a video of a planarian that is treated by RNAi against β-catenin and develops multiple heads instead of just one. This is one of the phenotypes that is inherited. Another phenotype is “loss of eyes” (which we show is not only inherited across multiple regeneration cycles, but can also be transmitted between animals in transplantation experiments). Amazing work led by first authors Prakash Cherian and Idit Aviram (co-supervised by Omri and me). Please read the preprint, the link is in the next tweet, and share!

"You have to focus on what you can do." Life advice from 2023 medicine laureate Katalin Karikó who is encouraging us all to focus on things that are within our control and pay less attention to what we can't control. For more life advice and to hear her life story, watch our full interview with her: youtu.be/X-jLB2cbdB8

There's no reason to confirm RNA-seq results with RT-PCR

I'll be in Europe in April & May for my annual "European tour", where I visit institutions to give talks to trainees about sci publishing & life as an editor, and meet w/PIs to discuss their work. I'm always looking for places to visit, so if you'd like to host me, let's talk!😊

Splice isoform-perturbation coupled to single cell transcriptome profiling reveals functions of microexons in neurogenesis and autism-linked pathways 🙌 nature.com/articles/s4146…

“Show me the mechanism of action.” “Uh. from the p-p-perturb seq? right here. Knocks down Gene X, and the cells shift into Cluster 7." “You used fkn UMAP again. FUCK. Zoom in.” “Sorry?” “Zoom. The fuck. In.” “…Okay.” “Do you see it?” “…See what?” “He doesn’t see it. The cell biology postdoc from Stanford does not know how to see a cell. He stares at a two-million-cell embedding and doesn’t see the conflations he just planted in my S3 bucket. WHERE is the temporal resolution?” “The… what?” “Where is the time? You hit the cell with a perturbation and you measured it once. Once. That’s not a mechanism. That’s a fucking POSTCARD!” “We sequenced at 72 hours. That’s standard.” “Standard is not the same as correct. You are aliasing causality. You compressed a dynamic process into a static endpoint and you’re think you will cure metastatic cancer.” “But the differential expression is significant.” “WOW! DIFFEWENTIAL EXPRESSION IS SIGNIFICANT! WOW! WHEN THE FUCK IS IT NOT. Yes, because statistics is Mario Kart. A fantasy land where causality is optional and variance disappears if you collect enough cells. Real biology has inertia. Feedback. Competing pathways. Do you understand the difference between correlation and mechanism? Or did you flunk out of STAT 101?” “…I mean, we saw Gene X regulate Pathway Y.” “No. You saw Pathway Y exist in the same cell after you kicked it down the stairs and waited three days. That’s not even a crime scene, you dimwit. That is a post-mortem autopsy.” “The model inferred a trajectory--” “STOP the buffoonery. Do not blame the model. The model is a mirror. In this particular case, you can see it mirrors the clusterfuck you just created in my biosafety cabinet. If the reflection is warped, it’s because your measurement is warped.” “Pull up the raw counts.” “…Okay.” “Scroll. Cell 14,982. Read it to me. What does it say?” “Uh… mitochondrial genes up, ribosomal genes down-” “And?” “…And stress response markers?” “Yes. Because you poisoned the cell and waited long enough for it to panic. Where is the early signaling? Where is the metabolic inflection? Where is the first irreversible decision?” “We don’t capture that.” “Exactly. You built a platform that cannot see the mechanism. YOUR PLATFORM IS FUCKING BLIND.” “The virtual cell...showed the perturbation effect cleanly.” “Yes. because your VIRTUAL CELL IS VIRTUAL. it assumes the cell is a bag of transcripts. Do you think metabolites show up? OR AN ISOFORM? AN ISOFORM, THAT WILL DEGRADE IN THE CELL BEFORE YOU EVER REACH YOUR SENSOR? THAT ONE? YOU THINK THAT'S HOW CELLS WORK?” “So what do you want me to do?” “Delete the atlas.” “What?” “Delete it. The whole thing.” “But that’s the core result.” “It’s three weeks of garbage narrative built on a blind instrument. Delete it.” “…Now what?” “Now you rebuild the measurement. You observe the cell while the perturbation propagates. You track chemistry, not just transcripts. You capture the first divergence, not the final corpse.” “That’s… not perturb-seq anymore.” “Exactly.” door slams

Would be perhaps useful to point out that neural organoids are not miniature brains and that they model fetal stages of parts of the human brain during development (rather than aging or rejuvenation). At these stages, especially in cortical organoids, neural activity is largely driven by spontaneous glutamatergic release and network synchronization typical of early circuits.

🚨 Fellowship Alert! 🌍 We’re offering multiple fellowships for students & postdocs to attend #mbiosys25 in Chile! Don’t miss this chance to join key discussions in gene regulation & functional genomics. 📆 Apply by April 30! 🔗 molbiosystems.com

Today we report in @CellStemCell a systematic approach to generate neural #organoids resembling various domains of the neural axis. @neal_amin & @kevinwkelley developed a multiplexed morphogen screen to generate hundreds of #organoids that ultimately transcriptionally mapped to almost 2/3 of the clusters in the 1st trimester human CNS Also led to generating surprising cell types, including the primate-enriched TAC3 neurons or Purkinje cells of the cerebellum (more on that soon) Check out the paper and summary below

Please RT: In my lab we are looking for computational #postdoc researchers to apply to a #juandelacierva or #embo postdoctoral fellowships to work on projects on post-transcriptional regulation on single-cell data (method development / data analysis). DM if you are interested.

Delighted to share new work from our lab: MultiPerturb-seq 🎛️❌📥📤 Over the last few years, we've been combining CRISPR screens with multimodal readouts of gene expression (RNA) and chromatin accessibility (DNA). In this study, we bring those together within the same cells.

Excited to share our latest work! We developed a new method for studying RNA localization via proximity labeling: OINC-seq! In contrast to other proximity methods, labels deposited on RNAs are read directly by sequencing without a need for biotinylation. biorxiv.org/cgi/content/sh…

Circular logic: understanding RNA’s strangest form yet nature.com/articles/d4158…

📅Save the date for our pioneering #Neurogenomics conference exploring neurodiversity, neurodevelopmental and neurodegenerative conditions! Connect with top researchers and explore cutting-edge developments through keynotes, talks, and discussions Info👉 humantechnopole.it/en/trainings/n…

-No puedo creer que los gringos hayan elegido a un presidente condenado -Los de linares

Thrilled to announce the release of our #community-driven model of rat #hippocampus. We worked with more than 50 researchers from 5 institutions & the result is out in @PLOSBiology 🔗journals.plos.org/plosbiology/ar… #simulation #neuroscience