It is shown that, unlike mammals, zebrafish can tolerate complete loss of Stag1 from embryogenesis through to adulthood, and it is proposed that modulation of growth and signalling pathways compensates for the absence of Stag1, allowing embryonic development to proceed correctly.
Abstract
Cohesin is a large multisubunit protein complex that plays essential roles in cell proliferation, genome organisation, and gene regulation in metazoans. Germline mutations in cohesin subunits or regulators cause a group of human developmental disorders collectively known as cohesinopathies. Increasing evidence indicates that individual cohesin subunits can confer distinct molecular functions to the complex; for example, STAG1 and STAG2 have both overlapping and non-overlapping roles in genome organisation. The zebrafish tailbud provides an excellent developmental model for investigating the coordination of cell proliferation and differentiation; processes in which cohesin has crucial functions. We previously demonstrated that loss of Stag2 disrupts Wnt signalling and mesoderm patterning in the zebrafish tailbud. Here, we show that, unlike mammals, zebrafish can tolerate complete loss of Stag1 from embryogenesis through to adulthood. In contrast to Stag2 deficiency, loss of Stag1 impairs cell cycle progression, activates p53 signalling, and induces a metabolic shift towards catabolism. BMP signalling is reduced in Stag1-deficient embryos and is accompanied by expansion of BMP antagonist chordin expression. Stag1 loss also alters chromatin accessibility at the chordin locus and affects accessibility at chromatin domain boundaries. We propose that modulation of growth and signalling pathways compensates for the absence of Stag1, allowing embryonic development to proceed correctly. Together, these findings reveal distinct contributions of Stag1 and Stag2 to cell-cycle regulation, chromatin architecture, and developmental signalling during vertebrate embryogenesis.
The essential and conserved role of Cbx3a/HP1γ in Nile tilapia spermatogenesis is clarified, thereby advancing the field of vertebrate reproductive epigenetics and providing a valuable theoretical basis for potential applications in reproductive management, such as improving sperm quality.
Cohesin complexes carrying either STAG1 or STAG2 display functional specificities in both cohesion and genome organization. While any variant is sufficient for cell viability, both are essential for murine embryonic development, and mutations in STAG1 and STAG2 are associated to human syndromes. The requirements and regulation of the cohesin variants in the first stages of development remain unknown. Here, we show that Stag1 and Stag2 gene products are stored in oocytes. Maternal STAG1 persists beyond the 2-cell stage while accumulation of STAG2 depends on zygotic transcription. Despite clear differences in STAG1:STAG2 ratio in the two lineages emerging from the first cell-fate decision, both maternal and zygotic STAG1 and STAG2 are dispensable for viability in preimplantation stages if the other variant is present. However, the absence of STAG2 increases DNA damage in zygotes and affects transcription in blastocysts. These early-stage alterations may contribute to defects leading to embryo lethality by mid-gestation.
Maria Solé-Ferran, Maria Jose Andreu, D. Giménez-Llorente et al.· Communications Biology· 0 citations
The development of multicellular organisms relies on the precise establishment and stable inheritance of cell type-specific transcriptional programs without changes to the underlying DNA sequence. Polycomb group (PcG) proteins are evolutionarily conserved epigenetic repressors that govern developmental gene expression by assembling into multiprotein complexes to establish robust and spatiotemporally restricted transcriptional silencing. Since their discovery through the classic Polycomb mutant phenotype in Drosophila melanogaster, PcG proteins have become a central paradigm for understanding epigenetic regulation during animal development. Here, we synthesize current knowledge of the molecular composition and functional organization of the core Polycomb repressive complexes (PRC1 and PRC2) and the accessory complexes PhoRC, PR-DUB, and dRAF, with particular emphasis on canonical hierarchical recruitment and emerging noncanonical regulatory mechanisms of Polycomb-mediated gene repression. We further summarize the dynamic roles of PcG proteins across the Drosophila life cycle, from embryonic patterning and larval organogenesis to metamorphic transition and adult tissue homeostasis. By integrating recent advances from Drosophila studies, this review provides a comprehensive overview of the molecular mechanisms and developmental functions of PcG proteins while highlighting future directions for investigating the conserved epigenetic mechanisms governing metazoan development.
The cohesin complex is a highly conserved, ring-shaped protein assembly that plays fundamental roles in chromosome biology. Originally identified as the molecular glue that holds sister chromatids together from DNA replication until cell division, cohesin has since been recognized as a pleiotropic regulator of genome organization, gene expression, DNA repair, and cell fate determination. In embryonic stem cells (ESCs), cohesin’s functions extend beyond canonical sister chromatid cohesion to include the maintenance of three-dimensional (3D) chromatin architecture through DNA loop extrusion, regulation of pluripotency-associated transcriptional programs, and facilitation of homologous recombination-mediated DNA repair during the prolonged S phase. Recent discoveries have revealed that meiosis-specific cohesin components, particularly the α-kleisin subunit REC8 and its interacting partner STAG3, are expressed and functionally active in mitotic ESC chromosomes, where they contribute to chromosomal organization and sister chromatid cohesion in concert with mitotic RAD21-containing cohesin. Furthermore, the interplay between cohesin and condensin complexes at shared genomic binding sites has emerged as a critical determinant of chromosome topology, with cohesin depletion leading to aberrant condensin accumulation and chromosome hypercompaction. Importantly, perturbations in cohesin function not only impair ESC self-renewal but also direct lineage-specific differentiation, linking cohesin to stem cell fate determination. Germline mutations in cohesin and its regulators underlie a spectrum of developmental disorders termed cohesinopathies, while somatic mutations are frequently observed in various cancers. This review provides a comprehensive overview of the diverse roles of cohesin in chromosome structure, cell cycle regulation, and stem cell biology, with particular emphasis on recent findings in ESCs that illuminate the complex interplay between mitotic and meiotic cohesin complexes.
Diverse genetic and epigenetic factors cooperate to specify cellular fates during development. Establishing these fates is especially critical in the nervous system, which comprises diverse neuronal cell types. How genomic architecture interfaces with epigenetic regulators to drive transcriptional programs underlying neuronal fates remains poorly understood. Here, we show that cohesin, a protein complex that shapes genomic architecture, promotes GABAergic fate specification in a subset of neurons in the nematode Caenorhabditis elegans. This process is facilitated by EOR-1, a homolog of the human promyelocytic leukemia zinc finger (PLZF) transcription factor. The nucleosome remodeling and deacetylase (NuRD) complex and TRA-4, another PLZF homolog, promote tyraminergic fate in the normally GABAergic neurons when cohesin or EOR-1 function is lost, revealing an antagonistic mechanism determining alternative neuronal fates. These findings highlight a critical interplay among genome architecture, epigenetic remodeling, and transcriptional regulation in neuronal fate specification and, given the evolutionary conservation of these factors, suggest a mechanism underlying neural development across species.
Dongyeop Lee, T. Hirose, H. R. Horvitz· Science Advances· 0 citations
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