SMCHD1's DNA binding activity enables its stable retention on chromatin

Authors

Hu, R., Sanchez-Velasquez, J., Lou, J., Breslin, K., Cameron, T., Solano, A., Wickramasinghe, I., Gouil, Q., Kueh, A. J., Willson, T., Keniry, A., Geoghegan, N. D., Hinde, E., Blewitt, M. E.

Abstract

Chromatin proteins play critical roles in gene regulation, yet frequently we do not fully understand how weak DNA binding affinity of such proteins contributes to their locus-specific actions. Here, we studied SMCHD1, a non-canonical SMC-family protein involved in three-dimensional genome organization and gene repression of the inactive X chromosome and its autosomal targets. We replaced endogenous SMCHD1 with GFP-tagged wild-type or hinge-domain DNA-binding mutant SMCHD1 to define the cellular role of DNA binding. The mutant showed reduced enrichment at the inactive X chromosome in female cells, while retaining stable binding at most autosomal binding sites. Impaired DNA binding weakens SMCHD1-mediated gene repression and chromatin-state regulation, producing hypomorphic effect. Multiple live-cell imaging methods reveal that DNA binding constrains SMCHD1 mobility and supports maintenance, rather than initial recruitment, of chromatin-bound SMCHD1 both during interphase and mitosis. Thus, SMCHD1's weak and sequence-independent DNA binding is a key determinant of its chromatin residence, localization and function. Our findings provide a framework for understanding SMCHD1 and other chromatin proteins with sequence-independent DNA binding activity.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 21 Sep 2026.

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