SMCHD1's DNA binding activity enables its stable retention on chromatin
- 1The Walter and Eliza Hall Institute of Medical Research
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.
Related
- Reversible chromatin remodeling enables Prosopis cineraria survival under recurrent heat extremes.
- A single-cell multimodal foundation model enables cross modality analysis between transcriptome and chromatin
- SPACE-Tag Enables High-Throughput Spatial Chromatin Profiling With CUT&Tag
- PKA disrupts adult ovarian identity circuits through direct inhibition of TRIM28-chromatin binding
- KAT3 Shuttling Between Neuronal Identity and Activity-Dependent Plasticity Programs Drives Large-Scale Chromatin Remodeling
BibTeX
@misc{hu2026smchd1s,
title = {{SMCHD1's DNA binding activity enables its stable retention on chromatin}},
author = {R. Hu and J. Sanchez-Velasquez and J. Lou and K. Breslin and T. Cameron and A. Solano and I. Wickramasinghe and Q. Gouil and A. J. Kueh and T. Willson and A. Keniry and N. D. Geoghegan and E. Hinde and M. E. Blewitt},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.14.751594},
url = {https://www.biorxiv.org/content/10.64898/2026.09.14.751594v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - SMCHD1's DNA binding activity enables its stable retention on chromatin
AU - R. Hu
AU - J. Sanchez-Velasquez
AU - J. Lou
AU - K. Breslin
AU - T. Cameron
AU - A. Solano
AU - I. Wickramasinghe
AU - Q. Gouil
AU - A. J. Kueh
AU - T. Willson
AU - A. Keniry
AU - N. D. Geoghegan
AU - E. Hinde
AU - M. E. Blewitt
PY - 2026
DA - 2026/09/14
PB - bioRxiv
DO - 10.64898/2026.09.14.751594
UR - https://www.biorxiv.org/content/10.64898/2026.09.14.751594v1
AB - 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.
ER -