A chromatin phase transition protects mitotic chromosomes against microtubule perforation

Dividing eukaryotic cells package extremely long chromosomal DNA molecules into discrete bodies to enable microtubule-mediated transport of one genome copy to each of the newly forming daughter cells[1][1]–[3][2]. Assembly of mitotic chromosomes involves DNA looping by condensin[4][3]–[8][4] and chromatin compaction by global histone deacetylation[9][5]–[13][6]. While condensin confers mechanical resistance towards spindle pulling forces[14][7]–[16][8], it is not known how histone deacetylation affects material properties and segregation mechanics of mitotic chromosomes. Here, we show how global histone deacetylation at the onset of mitosis induces a chromatin-intrinsic phase transition that endows chromosomes with specific characteristics necessary for their precise movement during cellular division. Deacetylation-mediated compaction of chromatin forms a structure dense in negative charge and allows mitotic chromosomes to resist perforation by microtubules as they are pushed to the metaphase plate. Hyperacetylated mitotic chromosomes lack a defined surface boundary, are frequently perforated by microtubules, and are prone to missegregation. Our study highlights the different contributions of DNA loop formation and chromatin-intrinsic phase separation to genome segregation in dividing cells. ### Competing Interest Statement M.K.R. is a co-founder of Faze Medicines. The other authors declare no competing interests. [1]: #ref-1 [2]: #ref-3 [3]: #ref-4 [4]: #ref-8 [5]: #ref-9 [6]: #ref-13 [7]: #ref-14 [8]: #ref-16