---
title: "SMCHD1 DNA binding is required for stable chromatin retention and repression"
id: "biorxiv-7-smchd1-s-dna-binding-activity-enables-its-stable-retention-on-chromatin"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-7-smchd1-s-dna-binding-activity-enables-its-stable-retention-on-chromatin"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.14.751594v1?rss=1"
published_at: "2026-09-20T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# SMCHD1 DNA binding is required for stable chromatin retention and repression
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-7-smchd1-s-dna-binding-activity-enables-its-stable-retention-on-chromatin
- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.14.751594v1?rss=1)
- **Published At:** 2026-09-20T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study examined how weak, sequence-independent **DNA binding** by SMCHD1 influences its chromatin localization and function. Researchers replaced endogenous SMCHD1 with GFP-tagged wild-type or a hinge-domain **DNA-binding mutant** to test in-cell effects. - The DNA-binding mutant showed reduced enrichment at the **inactive X chromosome** in female cells, while it largely retained stable binding at most autosomal SMCHD1 sites. - Impaired DNA binding produced a hypomorphic phenotype: weakened SMCHD1-mediated gene repression and altered chromatin-state regulation were observed when DNA binding was reduced. - Multiple live-cell imaging approaches demonstrated that DNA binding limits SMCHD1 mobility and is important for the maintenance of chromatin-associated SMCHD1, rather than for initial recruitment to chromatin sites. - This maintenance role of DNA binding was evident both during interphase and mitosis, indicating a cell-cycle–spanning function in retaining SMCHD1 on chromatin. - The findings support a model where **weak, sequence-independent DNA binding** is a key determinant of SMCHD1 residence time, localization specificity, and repressive activity, providing a framework for understanding other chromatin proteins with similar DNA interactions. - The work suggests locus-specific consequences of altered DNA binding: pronounced effects at the inactive X contrasted with relatively preserved autosomal binding, highlighting context-dependent reliance on DNA contacts. - Experimental details such as precise imaging modalities, quantitative mobility parameters, exact gene targets affected, and locus-level chromatin changes were described in the source but numerical values and specific datasets are not reproduced here; readers should consult the original preprint for full experimental data.
## Clinical Analysis & Structured Key Points
SMCHD1's DNA binding activity enables its stable retention on chromatin | bioRxiv Skip to main content New Results SMCHD1's DNA binding activity enables its stable retention on chromatin Ruifeng Hu , Julissa Sanchez-Velasquez , Jieqiong Lou , Kelsey Breslin , Tamara Cameron , View ORCID Profile Ashleigh Solano , Iromi Wickramasinghe , Quentin Gouil , Andrew J. Kueh , Tracy Willson , Andrew Keniry , Niall D Geoghegan , Elizabeth Hinde , View ORCID Profile Marnie E Blewitt doi: https://doi.org/10.64898/2026.09.14.751594 Ruifeng Hu 1 The Walter and Eliza Hall Institute of Medical Research; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Julissa Sanchez-Velasquez 2 The University of Melbourne; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jieqiong Lou 2 The University of Melbourne; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kelsey Breslin 1 The Walter and Eliza Hall Institute of Medical Research; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tamara Cameron 1 The Walter and Eliza Hall Institute of Medical Research; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ashleigh Solano 3 The Walter and Eliza Hall Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Ashleigh Solano Iromi Wickramasinghe 1 The Walter and Eliza Hall Institute of Medical Research; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Quentin Gouil 1 The Walter and Eliza Hall Institute of Medical Research; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrew J. Kueh 4 Walter and Eliza Hall Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tracy Willson 1 The Walter and Eliza Hall Institute of Medical Research; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrew Keniry 4 Walter and Eliza Hall Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Niall D Geoghegan 5 WEHI; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Elizabeth Hinde 6 University of Melbourne Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marnie E Blewitt 1 The Walter and Eliza Hall Institute of Medical Research; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Marnie E Blewitt For correspondence: blewitt{at}wehi.edu.au Abstract Info/History Metrics Supplementary material Preview PDF 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. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared National Health and Medical Research Council of Australia , 1194345 , 2041117 , 2007996 Pamela and Lorenzo Galli Trust Brian M Davis Charitable Trust Australian Research Council , DP180101387 , DP21010298 , LE210100046 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Back to top Previous Next Posted September 20, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following SMCHD1's DNA binding activity enables its stable retention on chromatin Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share SMCHD1's DNA binding activity enables its stable retention on chromatin Ruifeng Hu , Julissa Sanchez-Velasquez , Jieqiong Lou , Kelsey Breslin , Tamara Cameron , Ashleigh Solano , Iromi Wickramasinghe , Quentin Gouil , Andrew J. Kueh , Tracy Willson , Andrew Keniry , Niall D Geoghegan , Elizabeth Hinde , Marnie E Blewitt bioRxiv 2026.09.14.751594; doi: https://doi.org/10.64898/2026.09.14.751594 Share This Article: Copy Citation Tools SMCHD1's DNA binding activity enables its stable retention on chromatin Ruifeng Hu , Julissa Sanchez-Velasquez , Jieqiong Lou , Kelsey Breslin , Tamara Cameron , Ashleigh Solano , Iromi Wickramasinghe , Quentin Gouil , Andrew J. Kueh , Tracy Willson , Andrew Keniry , Niall D Geoghegan , Elizabeth Hinde , Marnie E Blewitt bioRxiv 2026.09.14.751594; doi: https://doi.org/10.64898/2026.09.14.751594 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Genomics Subject Areas All Articles Animal Behavior and Cognition (8013) Biochemistry (18739) Bioengineering (14888) Bioinformatics (44418) Biophysics (22599) Cancer Biology (19723) Cell Biology (26899) Clinical Trials (138) Developmental Biology (13965) Ecology (21005) Epidemiology (2067) Evolutionary Biology (25455) Genetics (16166) Genomics (23507) Immunology (18705) Microbiology (42503) Molecular Biology (18059) Neuroscience (93451) Paleontology (700) Pathology (2977) Pharmacology and Toxicology (5095) Physiology (8114) Plant Biology (15999) Scientific Communication and Education (2095) Synthetic Biology (4560) Systems Biology (10235) Zoology (2391)
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