Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains

Bryan, E., Valsakumar, D., Idigo, N.J., Warburton, M., Webb, K.M.,  McLaughlin, K.A., Spanos, C.,  Lenci, S., Major, V., Ambrosi, C., Andrews, S.,  Baubec, T., Rappsilber, J., and Voigt, P.

By Elena Hein, Bird Lab

Histone modifications regulate transcription by modulating DNA accessibility and recruiting activating or repressive chromatin factors. Nucleosomes may be marked symmetrically (monovalent), or asymmetrically (bivalent), thus controlling differential recruitment of histone mark readers. Promoters of developmental genes in embryonic stem cells (ESCs) are marked by bivalent nucleosomes, carrying both activating H3K4me3 and repressive H3K27me3, which is thought to maintain genes in a repressed yet activation-ready “poised” state. While the establishment of bivalency is fairly well understood, the exact mechanisms by which these domains keep genes in a poised state are still unclear.

In a recent paper published in Molecular Cell, Bryan et al. (2025) investigated how asymmetric bivalent nucleosomes influence reader recruitment. Using label-free quantitative mass spectrometry (LFQ-MS) -based nucleosome pull-down assays with mouse nuclear extracts, as well as recombinant symmetric and asymmetric nucleosomes, they found that bivalent nucleosomes preferentially recruited H3K27me3-binding repressive complexes while inefficiently recruiting H3K4me3-binding activators. Both activating and repressive readers were recruited less efficiently to bivalent nucleosomes than to their symmetric monovalent counterparts, but the researchers suggest that additional H3K27me3-independent nucleosome-binding properties of repressive complexes enhance their binding to asymmetric nucleosomes compared to activators, thus promoting a repressed state. 

The study also identified the acetyltransferase complex KAT6B as one of several bivalency-specific interactors. Functional assays revealed that KAT6B, and its less abundant paralogue KAT6A, are required for neuronal differentiation of mouse embryonic stem cells, acting to preserve the poised state of developmental genes.

These findings suggest that asymmetric bivalent histone modification patterns bias recruitment toward repression, influenced by additional H3K37me2-independent nucleosome binding affinities of repressive chromatin complexes. Identification of bivalency-specific readers such as KAT6B highlights additional layers of histone-based gene regulation and underscores the importance of reader-recruitment dynamics in controlling developmental gene expression programs.