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Today the paper led by our collaborators Iana Kim and Arnau Sebe-Pedrós lab in Barcelona got published in Nature: https://www.nature.com/articles/s41586-025-08960-w


Unsurprisingly, our contribution to this work, which deals with the origins of chromatin looping in animals, lies in DNA methylation. In a previous study, we sequenced the methylome of the ctenophore Mnemiopsis leidyi, which was quite puzzling. Unlike other invertebrates, gene bodies are not particularly enriched for 5mCG, and promoters are not unmethylated, which is typical of H3K4me3 marked regions. Instead, genes could have methylated "promoters" (proximal upstream regions to the start position of the gene), which were characterised with high repeat/Transposable Element content. Having methylated repeats in the promoter didn't seem to affect gene expression, as there were genes at all levels of expression that had these weird promoters.


Adapted from de Mendoza et al 2020, Nat Ecol Evol


At some point, I thought this was just an artifact of poor gene prediction, as perhaps those "promoters" were not really promoters but truncated gene models, but back then we didn't have the data to proof that....


Some years later, when Arnau's group obtained a new chromosome scale version of the Mnemiopsis leidyi genome, we improved gene annotation with a comprehensive approach and new methods, and checked methylation again. Still, 5mCG was found on those repeat-rich "promoter" regions. So how does that work? Well, it seems Ctenophores have a lot of chromatin loops, which put these genes with repeat-rich methylated promoters in contact with H3K4me3 marked distal "enhancers", which perhaps are playing the role of "promoters" in this species.


So how did ctenophores end up with this weird genomic configuration? It could be that methylation was targeted to repeats in general, also those colonising promoters, silencing them. This accumulation of junk on a sensitive regulatory region was then tolerated by looping over them. It could also be that the looping requires methylation, as the structural CTCF-like zinc fingers that mediate these loops seem to be methyl-sensitive. In sum, ctenophores represent a very interesting example of animals with methylation restricted to transposable elements, which show further links to 3D chromatin structure and genome regulation.


 
 
 

Jordana I.N. Oliveira obtained a Marie Skłodowska-Curie Actions fellowship to join our laboratory as a postdoc in 2025, to understand the evolutionary patterns of small RNAs and their potential link with viral endogenization across unicellular eukaryotes.


After our story about the unicellular-Sox made mouse, we have become "experts" in quirky mice phenotypes, so with Ben Tapon we got the chance to write a piece on the Woolly Mice generated by Colossal for The Conversation.


Thanks to a Royal Society Kan Tong Po Fellowship, I visited our collaborator's lab at Hong Kong University, where we talked about our follow up stories regarding the evolutionary history of Sox and POU transcription factors.

 
 
 

Updated: Dec 13, 2024

In this fantastic collaboration with the group of Ralf Jauch in Hong Kong University, we found out that Sox and POU genes, famous for their roles in stem cells, are older than previously thought. Not only that, but choanoflagellate Sox genes can substitute Sox2 when making mice induced pluripotent stem cells (iPSC). These, in turn, can contribute to make a chimeric mice, which we dubbed the "choano-mice". Then, we also reconstructed ancestral sequences in collaboration with the Hochberg group at the Max Plank, to find reveal that many of the ancestral Sox proteins have Sox2-like potential. Choanoflagellate POU is also remarkable, as very few species encode them, yet its DNA binding specificity is still very much like most homeodomains, not yet binding to the octamer, the preferred motif for animal POU orthologues. See the paper here:



This research has sparked quite an unexpected love from the media outlets, and we got covered in several venues, including the Washington Post and Forbes:


All the way to a funnily titled version in a British tabloid:

 
 
 

© 2020 by Alexandre de Mendoza

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