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This study investigates how SMCHD1, a chromatin protein involved in gene regulation and X-chromosome inactivation, uses DNA binding to maintain its position on chromosomes. Researchers created mutant versions of SMCHD1 with impaired DNA binding and found that while the protein could still be initially recruited to chromatin, its DNA binding activity was essential for stable retention at binding sites, particularly on the inactive X chromosome. Live-cell imaging revealed that DNA binding reduces SMCHD1 mobility and is critical for maintaining its chromatin localization during both interphase and mitosis, which in turn affects gene repression and chromatin organization.
Why it matters
Understanding how chromatin proteins like SMCHD1 stably associate with DNA has implications for comprehending gene regulation mechanisms and diseases linked to SMCHD1 mutations, including certain developmental disorders and cancers. This work provides a framework for studying other chromatin proteins that bind DNA without sequence specificity, which could inform therapeutic strategies targeting chromatin regulation.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.
Source: SMCHD1's DNA binding activity enables its stable retention on chromatin