Biology subjects

Losi, F.

Publications and source records attributed to Losi, F..

3 recordsLinked to original sources

bioRxiv2026

Stage-dependent chromatin accessibility remodeling defines an architectural state in facioscapulohumeral muscular dystrophy myoblasts

Facioscapulohumeral muscular dystrophy (FSHD) has been linked to alterations in higher-order genome organization, yet how these structural perturbations shape chromatin accessibility across muscle developmental stages remains unclear. Here, we identify a stage-specific architectural chromatin accessibility state that defines proliferating FSHD myoblasts. Using genome-wide ATAC-seq profiling of primary human myoblasts and differentiated myotubes, analyzed using the telomere-to-telomere (T2T-CHM13) human reference genome, we map the genome-wide distribution and hierarchical organization of this state. We detect extensive chromatin accessibility remodeling, with over 12,000 differentially accessible regions in myoblasts and marked attenuation of this state upon terminal differentiation. Remodeling predominantly affects intronic and distal intergenic regions enriched in non-coding and repeat-proximal sequences, indicating redistribution of regulatory accessibility beyond promoter-centered regulation. At the chromosome scale, accessibility losses cluster within megabase domains enriched in heterochromatin- and nucleolus-associated regions, revealing coordinated reorganization of nuclear architecture. No reproducible accessibility changes occur within the D4Z4 repeat array or canonical DUX4 target loci, demonstrating that early architectural remodeling in FSHD myoblasts is largely uncoupled from sustained DUX4-driven programs. These findings these findings define a transient architectural chromatin accessibility state that emerges in proliferating FSHD myoblasts and is largely resolved upon terminal differentiation. Our work supports a model in which disruption of higher-order genome organization represents an early and stage-restricted determinant of disease susceptibility.

genomics↗

bioRxiv2024

A novel family of lncRNAs relate facioscapulohumeral muscular dystrophy to nucleolar architecture and protein synthesis rate

Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary myopathy linked to deletions of the tandemly arrayed D4Z4 macrosatellite repeats at human chromosome 4q35. These deletions accompany local chromatin changes and the anomalous expression of nearby transcripts FRG2A, DBET, and D4Z4. We discovered that FRG2A is one member of a family of long non-coding RNAs (lncRNAs) expressed at elevated levels in skeletal muscle cells with distinct amounts detected in individual patients. We found that FRG2A lncRNA preferentially associates with rDNA sequences and centromeres and promotes the three-dimensional association of centromeres with the nucleolar periphery in FSHD cells. Furthermore, we demonstrate that the elevated FRG2A expression in cells from FSHD patients reduces rDNA transcription and global protein synthesis. Our results frame an entirely unanticipated new disease model in which elevated lncRNAs levels mediated by deletions of D4Z4 macrosatellite repeats leads to a diminished protein synthesis capacity, thereby contributing to muscle wasting.

molecular biology↗

bioRxiv2024

Post-transcriptional RNA stabilization of telomere-proximal RNAs FRG2, DBET, D4Z4 at human 4q35 in response to genotoxic stress and D4Z4 macrosatellite repeat length.

BackgroundReduced copy number of the D4Z4 macrosatellite at human chromosome 4q35 is associated with facioscapulohumeral muscular dystrophy (FSHD). A pervasive idea is that chromatin alterations at the 4q35 locus following D4Z4 repeat unit deletion lead to disease via inappropriate expression of nearby genes. Here, we sought to analyze transcription and chromatin characteristics across 4q35 and how these are affected by D4Z4 deletions and exogenous stresses. ResultsWe found that the 4q subtelomere is subdivided into discrete domains, each with characteristic chromatin features associated with distinct gene expression profiles. Centromere-proximal genes within 4q35 (ANT1, FAT1 and FRG1) display active histone marks at their promoters. In contrast, poised or repressed markings are present at telomere-proximal loci including FRG2, DBE-T and D4Z4. We discovered that these discrete domains undergo region-specific chromatin changes upon treatment with chromatin enzyme inhibitors or genotoxic drugs. We demonstrated that the 4q35 telomere-proximal FRG2, DBE-T and D4Z4-derived transcripts are induced upon DNA damage to levels inversely correlated with the D4Z4 repeat number, are stabilized through post-transcriptional mechanisms upon DNA damage, and are bound to chromatin. ConclusionOur study reveals unforeseen biochemical features of RNAs from clustered transcription units within the 4q35 subtelomere. Specifically, the FRG2, DBE-T and D4Z4-derived transcripts are chromatin-associated and are stabilized post-transcriptionally after induction by genotoxic stress. Remarkably, the extent of this response is modulated by the copy number of the D4Z4 repeats, raising new hypotheses about their regulation and function in human biology and disease.

genetics↗