So many memories and feelings cleaning up boxes... Where do the unfinished projects go? Are the amount of plastic tubes used worth the discoveries? Also, this picture could serve as my CV...

Deletion of LTR5Hs ZNF729 decreased cell proliferation. In agreement, we show that ZNF729 regulates cell proliferation genes. Other housekeeping genes are also regulated, presumably via ZNF729 binding to G/C rich sequences, very abundant at gene promoters associated with basic cellular functions.

To our surprise, ChIP-seq experiments (validated with dTAG-acute depletions) revealed that ZNF729 binds close to 50 K genomic regions in naïve PSCs. As expected, it binds transposable elements…but it binds even more to gene promoters! These promoters are G/C-rich.

To investigate the function of this novel protein, we engineered human naïve pluripotent stem cells adding a degron and an HA tag. Interestingly, ZNF729 is the KZFP with the highest number of zinc-finger domains: 37!

This LTR5Hs insertion activates the expression of a KRAB Zinc Finger transcription factor: ZNF729. This TF is very young too: primate-specific! And our analyses indicate that it is not expressed in rhesus’ or chimpanzee’s naïve pluripotency.

Using genetic deletions of LTR5Hs insertions, we discovered that an LTR5Hs copy, exclusive to humans, is essential for blastoid formation (!!!). But how?

Remarkably, comparison between the genes regulated by LTR5Hs in blastoids and the genes expressed in the mouse epiblast reveals that the HERVK invasion diversified the epiblast transcriptome in humans.

Using IFs and scRNA-seq we demonstrate that LTR5Hs repression drives gene expression changes in the blastoids epiblast. Comparisons with human embryo data suggest these changes represent a defect in maturation. In agreement, we also detected a reduction of hypoblast cells.

We repressed HERVK LTR5Hs en masse using CARGO LTR5Hs. This revealed that LTR5Hs activity affects the blastoid-forming potential in a dose-dependent manner. We analyzed > 20 clones for each condition (equivalent to ~140 K human blastoids! Close to the population of my hometown León…😂)

To answer this question, we used as a model the youngest ERV in our genome: HERVK LTR5Hs. HERVK LTR5Hs is active from the 8-cell stage, and it peaks in the blastocyst. It invaded the genome in hominoids, but some insertions are specific to humans and even polymorphic in the population.

I am thrilled to share our preprint where we take advantage of the unique opportunities offered by human blastoids to uncover a human-specific mechanism potentially playing a role in preimplantation 🧵. www.biorxiv.org/content/10.1...

I am thrilled to be a speaker at Sy-stem among scientists I truly admire. Fantastic lineup of #stemcell researchers in the beautiful Vienna! Registration and more information here: www.sy-stem.org