Thank you Kaushik!

It’d be so cool to screen evolutionarily divergent CENP-A and map effects on centromere organization!

Thank you!

Thank you so much!

One last thing - I am on the job market! My lab will extend this approach to decode resilient chromatin: adaptations in proteins/DNA that allow for survival in harsh environments. These hold the 🔑 to designing cells that thrive under stress, esp. as we push the limits of where we take them ❄️🚀🪐🌱9/9

Huge thanks to all co-authors and the inimitable @jbuenrostro.bsky.social for supporting this new direction - I got to think about evolution, engineering, chromatin biophysics, and modeling during the course of this project. For more, check out the preprint: www.biorxiv.org/content/10.1... 8/9

This work is a proof of concept towards fully programmable chromatin, something I think will become very common. By combining evolutionary insights, high-throughput assays and predictive/generative modeling, we should be able to uncover some true “superpowers” of chromatin (more on this soon!) 7/9

Finally, we set out to achieve what I’d always wanted. Using screen data and sequence embeddings, we trained a classifier to predict heterochromatin repression, and used it to design totally synthetic histones we called synH4s that demonstrate optimized heterochromatin-repressing activity. 6/9

This process was able to alter cellular plasticity to transcription factor inputs: T cells expressing the tail mutant G4D displayed increased accessibility of heterochromatin-associated transcription factors and were able to respond to overexpression of those factors with proliferation! 5/9

We were surprised to see that some mutations in the N-terminal tail of H4 caused outsized effects on chromatin structure- digging in deeper, we found that these mutations alter nucleosomes in cis, ablating the heterochromatin mark H3K9me3 and shaping spatial compartmentalization in the nucleus. 4/9

The first step was defining sequence-to-function relationships. To do this, we turned to high-throughput screening of 1000s of variants for effects on chromatin accessibility and histone marks. We found that some single-residue changes have global effects on chromatin structure! 3/9

Organisms across the tree of life, including humans, have evolved histone sequences that remodel chromatin in diverse ways. As I learned about these examples, I grew mildly obsessed with the idea of designing histones to do what *I* wanted them to do. 2/9