The cohesin complex plays an essential role in maintaining genome organization. However, its role in gene regulation remains largely unresolved. Here, we report that the cohesin release factor WAPL creates a pool of free cohesin, in a process known as cohesin turnover, which reloads it to cell-type specific binding sites. Paradoxically, stabilization of cohesin binding, following WAPL ablation, results in depletion of cohesin from these cell-type specific regions, a loss of gene expression and differentiation. Chromosome conformation capture experiments show that cohesin turnover is important for maintaining promoter-enhancer loops. Binding of cohesin to cell-type specific sites is dependent on the pioneer transcription factors OCT4 (POU5F1) and SOX2, but not NANOG. We show the importance of cohesin turnover in controlling transcription and propose that a cycle of cohesin loading and off-loading, instead of static cohesin binding, mediates promoter and enhancer interactions critical for gene regulation.
An increasing body of evidence highlights an intriguing interaction between microRNAs and transcriptional factors involved in determining cell fate, including the well known “genome guardian” p53. Here we show that miR-205, oncosuppressive microRNA lost in breast cancer, is directly transactivated by oncosuppressor p53. Moreover, evaluating miR-205 expression in a panel of cell lines belonging to the highly aggressive triple negative breast cancer (TNBC) subtype, which still lacks an effective targeted therapy and characterized by an extremely undifferentiated and mesenchymal phenotype, we demonstrated that this microRNA is critically down-expressed compared to a normal-like cell line. Re-expression of miR-205 where absent strongly reduces cell proliferation, cell cycle progression and clonogenic potential in vitro, and inhibits tumor growth in vivo, and this tumor suppressor activity is at least partially exerted through targeting of E2F1, master regulator of cell cycle progression, and LAMC1, component of extracellular matrix involved in cell adhesion, proliferation and migration.
Despite advances in detection and therapies, breast cancer is still the leading cause of cancer death in women worldwide. The etiology of this neoplasm is complex, and both genetic and environmental factors contribute to the complicate scenario. Gene profiling studies have been extensively used over the last decades as a powerful tool to define the signature of different cancers and to predict outcome and response to therapies. More recently, a new class of small (19-25 nucleotides) non-coding RNAs, microRNAs (miRs or miRNAs) has been linked to several human diseases, included cancer. MicroRNAs are involved in temporal and tissue-specific eukaryotic gene regulation,(1) either by translational inhibition or exonucleolytic mRNA decay, targeted through imperfect complementarity between the microRNA and the 3' untranslated region (3'UTR) of the mRNA.(2) Since their ability to potentially target any human mRNA, it is likely that microRNAs are involved in almost every biological process, including cell cycle regulation, cell growth, apoptosis, cell differentiation and stress response.(3) The involvement of microRNAs in the biology of human cancer is supported by an increasing body of experimental evidence, that has gradually switched from profiling studies, as the first breast cancer specific signature reported in 2005 by our group(4) describing an aberrant microRNA expression in different tumor types, to biological demonstrations of the causal role of these small molecules in the tumorigenic process, and the possible implications as biomarkers or therapeutic tools.(5) These more recent studies have widely demonstrated that microRNAs can modulate oncogenic or tumor suppressor pathways, and that, at the same time, their expression can be regulated by oncogenes or tumor suppressor genes. The possibility to modulate microRNA expression both in vitro and in vivo by developing synthetic pre-microRNA molecules or antisense oligonucletides has at the same time provided a powerful tool to a deeper comprehension of the molecular mechanisms regulated by these molecules, and suggested the intriguing and promising perspective of a possible use in therapy. Here we review our current knowledge about the involvement of microRNAs in cancer, focusing particularly on breast cancer, and their potential as diagnostic, prognostic and therapeutic tools.
Orchestrating vertebrate genomes require a complex interplay between the linear composition of the genome and its 3D organization inside the nucleus. This requires the function of specialized proteins, able to tune various aspects of genome organization and gene regulation. The CCCTC-binding factor (CTCF) is a DNA binding factor capable of regulating not only the 3D genome organization, but also key aspects of gene expression, including transcription activation and repression, RNA splicing, and enhancer/promoter insulation. A growing body of evidence proposes that CTCF, together with cohesin contributes to DNA loop formation and 3D genome organization. CTCF binding sites are mutation hotspots in cancer, while mutations in CTCF itself lead to intellectual disabilities, emphasizing its importance in disease etiology. In this review we cover various aspects of CTCF function, revealing the polyvalence of this factor as a highly diversified tool for vertebrate genome organization and transcription regulation.
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