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

Chromatin proteins play a crucial role in regulating genes, but their mechanism of action, especially with weak DNA binding affinity, remains unclear. This study focuses on SMCHD1, a non-canonical SMC-family protein that participates in three-dimensional genome organization and the repression of genes on the inactive X chromosome and its autosomal targets.

Researchers replaced the native SMCHD1 with a GFP-tagged wild-type or a hinge-domain DNA-binding mutated version to determine the role of DNA binding. The mutated form exhibited lower accumulation at the inactive X chromosome in female cells, yet maintained stable binding at most autosomal sites. The DNA binding capability of SMCHD1 weakens its ability to repress genes and regulate chromatin states, resulting in a hypomorphic effect.

Through various live-cell imaging techniques, the study found that DNA binding restricts SMCHD1's mobility and aids in maintaining its chromatin-bound state, both during interphase and mitosis. The conclusion is that the weak and sequence-independent DNA binding of SMCHD1 is a critical factor in determining its chromatin residence, localization, and function.

This research provides a foundation for understanding other chromatin proteins with similar DNA binding characteristics.