Millions suffer from intellectual disability (ID) syndromes, a class of neurodevelopmental diseases wherein the primary manifestation is lower cognitive function. While some ID results from environmental factors, many are the outcome of genetic mutations altering regulatory processes involved in regular brain development. Rett Syndrome is an X-linked ID syndrome whose classical form results from a mutation in the MECP2 gene: an epigenetic reader protein mainly involved in transcriptional regulation through chromatin remodeling. Recently, our group has identified DNA damage as a driving force of Rett in vitro, the repair of which reduces many of the metabolic and dendritic dysfunctions disrupting neuronal activity. Nonetheless, little is known about the specific proteins whose disruption in vivo may prevent DNA repair and stimulation may promote it. In this work, we target DNA repair proteins via immunostaining in the rat brain in conjunction with computational protein networks to determine how DNA damage repair is altered in Rett Syndrome. We find MECP2-null neurons show consistent reductions in DNA repair molecules, including 53BP1, RNA Polymerase II, and pATR, indicating reductions in DNA repair in vivo. Furthermore, computational analysis of MECP2 protein interactors through biological networks and gene ontology (GO) has identified ten other neurological disorders potentially driven by DNA damage, suggesting commonality among a subset of monogenic ID syndromes.

During the development of multicellular organisms, pluripotent stem cells differentiate into specialized cell types with distinct functions. In mammals, this transition is regulated by the mammalian BAF chromatin remodeling complex, which modifies chromatin structure to facilitate lineage-specific gene expression. Specific combinations of the BAF complex subunits have been implicated to be developmental-stage specific and linked to cell lineage commitment. In this study, we characterized the changes in the composition of the BAF complex across different stages of muscle development. We differentiated C2C12 myoblasts to mature myotubes and compared the BAF subunit compositions to that of embryonic stem cells. We found that the incorporation of key subunits, including BRG1, BAF60a, and BAF60c, is differentially regulated in the three stages. We also identified distinct subunit changes during differentiation, including a switch around 170 kDa. The study highlights the dynamic nature of the BAF complex during skeletal muscle development, providing insights into the mechanisms of transcriptional regulation and disease therapeutics.

Tight regulation of gene expression programs is vital for cell survival and occurs through dynamic, interconnected mechanisms. Saccharomyces cerevisiae, also known as baker’s yeast, is a biochemically and genetically tractable organism that has provided an excellent model for understanding highly conserved gene regulation mechanisms. In both yeast and mammals, the SWI/SNF chromatin remodeling complex is involved in the regulation of many genes required for growth, differentiation, and responses to environmental cues. The activity of the catalytic subunit of the SWI/SNF complex, known as Snf2 in yeast, is required for gene regulation mechanisms in all of the aforementioned processes. However, it is not understood how the SNF2 gene itself is regulated. We show two RNA isoforms for the SNF2 gene that have distinct roles in regulating Snf2 protein levels. We have found that overall glucose availability influences preferential transcription of either isoform. Furthermore, experiments in a reporter system have shown that transcription of the longer isoform actively decreases Snf2 protein expression. Altogether this corroborates a model whereby glucose deprivation leads to preferential transcription of the long SNF2 RNA isoform which acts to decrease translation of Snf2. Future research may explore the extent to which this mechanism is conserved in humans and apply our model to explore SWI/SNF mediated gene regulation in higher eukaryotes.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) affects 30% of the global population. MASLD risk and progression are influenced by biological sex, which is composed of gonadal type and sex chromosomes. Both gonadal sex (ovaries vs. testes) and chromosomal sex (XX vs. XY) can uniquely impact disease mechanisms, but the independent contribution of each sex component in MASLD remains unclear. To evaluate these differences, we used the Four Core Genotypes mouse model, which independently segregates gonads and sex chromosomes to generate XX and XY mice, each with ovaries or testes. We induced MASLD using a high-fat diet for 10 weeks and evaluated the transcriptome, proteome, lipidome, and metabolome. To confirm gonadal hormone effects, we assessed a separate mouse cohort that was gonadectomized as adults to remove circulating hormones. Hepatic gene expression, as well as protein, lipid, and metabolite levels, were influenced by both gonadal type and sex chromosome complement through distinct metabolic, immune, and signaling pathways. Additionally, gene co-expression analysis revealed modules associated with each sex component, identifying gene networks that reveal relationships among groups of genes. Analysis of mice that had undergone gonadectomy confirmed gonadal hormone effects and exposed a larger sex chromosome impact on gene expression. These findings highlight sex-biased mechanisms of gene regulation, which offer new insights into disease pathogenesis and potential for personalized therapeutic strategies.