Biology subjects

Cameron, T.

Publications and source records attributed to Cameron, T..

4 recordsLinked to original sources

bioRxiv2026

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

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.

genomics↗

bioRxiv2026

Regulation of Human Erythroferrone Expression

Erythroferrone (ERFE) is an erythroblast-secreted hormone that suppresses hepatic hepcidin expression to increase iron availability for erythropoiesis, ensuring recovery from anaemia. ERFE excess drives iron overload in disorders of ineffective erythropoiesis. Despite its pivotal role in systemic iron homeostasis and diseases of erythropoiesis, ERFEs molecular regulation has remained undefined. Here, we applied a genomic approach to characterise the molecular mechanisms governing ERFE expression. Using the HUDEP-2 human erythroid progenitor model, integrative ATAC-seq, CUT&RUN and micro capture-C analysis we identified a stage-specific accessible chromatin region within the ERFE 3 UTR that interacts with the promotor. We also identified enhancer-associated chromatin marks including H3K4me1 and H3K27ac in this region, and demonstrate that this cis-regulatory element is bound by key erythroid transcription factors KLF1, GATA1, TAL1 and STAT5. Functional dissection using CRISPR-Cas9-mediated deletion of the central 3 UTR enhancer element led to marked reduction in ERFE mRNA expression, and we show a corresponding reduction in nascent mRNA, confirming a key role for this region in transcriptional regulation. We define the transcriptional regulatory mechanism by which maturing human erythroblasts activate ERFE, the endocrine signal that coordinates erythropoietic demand with systemic iron mobilisation.

molecular biology↗

bioRxiv2026

SMCHD1 is a novel target for gene-activation therapy to treat Prader-Willi Syndrome

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by lack of gene expression from the active paternal allele at an imprinted gene cluster on chromosome 15. Current treatments have limited efficacy as they target individual symptoms rather than the underlying cause of disease. All patients preserve a normal, yet epigenetically-silenced, copy of the PWS cluster genes; activation of this imprinted copy to restore necessary gene expression is an appealing option for tackling the root of the disorder. Here we have addressed the potential to activate these silent maternal genes by targeting the epigenetic regulator Structural Maintenance of Chromosomes Hinge domain containing 1 (SMCHD1). First, we expanded the role of SMCHD1 in repressing the PWS cluster from mice to humans, a critical step if SMCHD1 is to be a drug target. Second, we discovered that SMCHD1 represses the entire PWS locus in neural lineages, extending its previously known role at only half of the PWS genes. We show that deleting Smchd1 after early development in vivo is effective at causing PWS gene-activation in disease-relevant mouse tissues including hypothalamus, and that this has beneficial effects on phenotypes observed in a PWS mouse model. Despite SMCHD1 having a role in gene silencing elsewhere in the genome, our data suggest that targeting SMCHD1 after early development is remarkably safe. Taken together, these data propose SMCHD1 as a novel target for gene-activation therapy for PWS.

genetics↗

bioRxiv2026

DNA binding by ATPase-adjacent domains stimulates SMCHD1 ATPase activity

SMCHD1 is an epigenetic regulator in which heterozygous variants are reported in facioscapulohumeral muscular dystrophy (FSHD), as well as Bosma arhinia microphthalmia syndrome (BAMS). While we have previously shown that SMCHD1 is able to interact with nucleic acids via its hinge domain, we have now identified a second DNA-binding site that is located C-terminal to the ATPase domain and formed by two domains: the Bromo-adjacent homology (BAH) and immunoglobulin-like 1 (IGL-1) domains. Here, we report their mode of DNA-interaction and we present the first high-resolution structure of the wild-type human SMCHD1 ATPase using site-directed mutagenesis and structural analysis via cryo-EM. We also reveal that DNA-binding at the BAH-IGL-1 domains stimulates the ATPase activity of full-length SMCHD1 in vitro, and demonstrate in a mouse model that ATP hydrolysis is essential for SMCHD1 function in vivo. Together, these findings establish bidentate DNA binding and DNA-stimulated ATP hydrolysis as central features of SMCHD1 function, providing new mechanistic insight into how SMCHD1 regulates gene silencing. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/704097v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@12b2fd5org.highwire.dtl.DTLVardef@5152c7org.highwire.dtl.DTLVardef@111c487org.highwire.dtl.DTLVardef@17d8d0d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗