Biology subjects

Balog, J.

Publications and source records attributed to Balog, J..

3 recordsLinked to original sources

bioRxiv2024

Lrif1 modulates Trim28-mediated repression of the Dux locus in mouse embryonic stem cells

Germline mutations in SMCHD1, DNMT3B and LRIF1 can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2). FSHD is an epigenetic skeletal muscle disorder in which partial failure in heterochromatinization of the D4Z4 macrosatellite repeat causes spurious expression of the repeat-embedded DUX4 gene in skeletal muscle, ultimately leading to muscle weakness and wasting. All three proteins play a role in chromatin organization and gene silencing; however, their functional relationship has not been fully elucidated. Here, we show that knockdown of Lrif1, but not of the other two FSHD2 genes, in mouse embryonic stem cells leads to modest upregulation of the 2-cell cleavage stage transcriptional program driven by the transcription factor Dux, which is the mouse functional homologue of human DUX4. Furthermore, we show that Lrif1 interacts with Trim28, a known Dux repressor and that this interaction is independent of Cbx proteins and Smchd1. We uncover that modest Dux upregulation in Lrif1 knockdown mESCs coincides with decreased Trim28 occupancy at the Dux locus. Together, our results provide evidence for a conserved function of Lrif1 in repressing an early zygotic genome activator in mice and humans.

molecular biology↗

bioRxiv2024

SUMOylation differentially regulates SMCHD1 complex formation and function in a genomic context-specific manner

Structural Maintenance of Chromosomes Hinge Domain Containing 1 (SMCHD1) is a chromatin repressor regulating gene expression and chromatin architecture of distinct autosomal and X-chromosomal loci. SMCHD1 mutations cause derepression of the D4Z4 macrosatellite repeat-embedded DUX4 gene in skeletal muscle of facioscapulohumeral muscular dystrophy (FSHD) patients Little is known about the regulation and post-translational modification of SMCHD1. Here we report the SUMOylation dynamics of SMCHD1 and its impact on autosomal single copy and repetitive loci, and the inactive X chromosome (Xi). We identify that SMCHD1 is SUMOylated primarily at lysine 1374, uncover factors regulating SMCHD1 SUMOylation, and demonstrate that SMCHD1 interacts with chromatin repressors TRIM28, HNRNPK and SETDB1 in a SUMO-dependent manner. We find that SUMOylation impacts Xi engagement of SMCHD1, maintenance of a repressive D4Z4 chromatin structure preventing DUX4 expression, and regulation of LRIF1 promoter activity. The rapid, SUMO-dependent upregulation of DUX4 could explain the bursts of DUX4 expression typical for FSHD muscle.

molecular biology↗

bioRxiv2019

Social hierarchy regulates ocular dominance plasticity in adult male mice.

We here show that social rank, as assessed by competition for a running wheel, influences ocular dominance plasticity in adult male mice. Dominant animals showed a clear ocular dominance shift after four days of MD, whereas their submissive cage mates did not. NMDA receptor activation, reduced GABA inhibition, and serotonin transmission were necessary for this plasticity, but not sufficient to explain the difference between dominant and submissive animals. In contrast, prefrontal dopamine concentration was higher in dominant than submissive mice, and systemic manipulation of dopamine transmission bidirectionally changed ocular dominance plasticity. Thus, we could show that a social hierarchical relationship influences ocular dominance plasticity in the visual cortex via higher-order cortices, most likely the medial prefrontal cortex. Further studies will be needed to elucidate the precise mechanisms by which this regulation takes place.

neuroscience↗