The multifaceted roles of cohesin in cancer.

The cohesin complex controls faithful chromosome segregation by pairing sister chromatids after DNA replication until mitosis. In addition, it is crucial for hierarchal three-dimensional organization of the genome, transcription regulation and maintaining DNA integrity. The core complex subunits SMC1A, SMC3, STAG1/2, and RAD21 as well as its modulators, have been found to be recurrently mutated in human cancers. The mechanisms by which cohesin mutations trigger cancer development and disease progression are still poorly understood. Since cohesin is involved in a range of chromosome-related processes, the outcome of cohesin mutations in cancer is complex. Herein, we discuss recent discoveries regarding cohesin that provide new insight into its role in tumorigenesis.

Disease-associated c-MYC downregulation in human disorders of transcriptional regulation.

Cornelia de Lange syndrome (CdLS) is a rare multiorgan developmental disorder caused by pathogenic variants in cohesin genes. It is a genetically and clinically heterogeneous dominant (both autosomal and X-linked) rare disease. Increasing experimental evidence indicates that CdLS is caused by a combination of factors, such as gene expression dysregulation, accumulation of cellular damage and cellular aging, which collectively contribute to the CdLS phenotype. The CdLS phenotype overlaps with a number of related diagnoses such as KBG syndrome and Rubinstein-Taybi syndrome both caused by variants in chromatin-associated factors other than cohesin. The molecular basis underlying these overlapping phenotypes is not clearly defined. Here, we found that cells from individuals with CdLS and CdLS-related diagnoses are characterized by global transcription disturbance and share common dysregulated pathways. Intriguingly, c-MYC (subsequently referred to as MYC) is downregulated in all cell lines and represents a convergent hub lying at the center of dysregulated pathways. Subsequent treatment with estradiol restores MYC expression by modulating cohesin occupancy at its promoter region. In addition, MYC activation leads to modification in expression in hundreds of genes, which in turn reduce the oxidative stress level and genome instability. Together, these results show that MYC plays a pivotal role in the etiopathogenesis of CdLS and CdLS-related diagnoses and represents a potential therapeutic target for these conditions.

Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach.

Cornelia de Lange syndrome (CdLS) is a severe genetic disorder characterised by multisystemic malformations. CdLS is due to pathogenetic variants in NIPBL, SMC1A, SMC3, RAD21 and HDAC8 genes which belong to the cohesin pathway. Cohesin plays a pivotal role in chromatid cohesion, gene expression, and DNA repair. In this review, we will discuss how perturbations in those biological processes contribute to CdLS phenotype and will emphasise the state-of-art of CdLS therapeutic approaches.

Chlorpyrifos exposure affects fgf8, sox9, and bmp4 expression required for cranial neural crest morphogenesis and chondrogenesis in Xenopus laevis embryos.

Chlorpyrifos (CPF) is an organophosphate insecticide used primarily to control foliage and soil-borne insect pests on a variety of food and feed crops. In mammals, maternal exposure to CPF has been reported to induce dose-related abnormalities such as slower brain growth and cerebral cortex thinning. In lower vertebrates, for example, fish and amphibians, teratogenic activity of this compound is correlated with several anatomical alterations. Little is known about the effects of CPF on mRNA expression of genes involved in early development of the anatomical structures appearing abnormal in embryos. This study investigated the effects of exposure to different CPF concentrations (10, 15 and 20 mg/L) on Xenopus laevis embryos from stage 4/8 to stage 46. Some of the morphological changes we detected in CPF-exposed embryos included cranial neural crest cell (NCC)-derived structures. For this reason, we analyzed the expression of select genes involved in hindbrain patterning (egr2), cranial neural crest chondrogenesis, and craniofacial development (fgf8, bmp4, sox9, hoxa2 and hoxb2). We found that CPF exposure induced a reduction in transcription of all the genes involved in NCC-dependent chondrogenesis, with largest reductions in fgf8 and sox9; whereas, in hindbrain, we did not find any alterations in egr2 expression. Changes in the expression of fgf8, bmp4, and sox9, which are master regulators of several developmental pathways, have important implications. If these changes are confirmed to belong to a general pattern of alterations in vertebrates prenatally exposed to OP, they might be useful to assess damage during vertebrate embryo development. Environ. Mol. Mutagen. 57:589-604, 2016. © 2016 Wiley Periodicals, Inc.

Short interspersed DNA elements and miRNAs: a novel hidden gene regulation layer in zebrafish?

In this study, we investigated by in silico analysis the possible correlation between microRNAs (miRNAs) and Anamnia V-SINEs (a superfamily of short interspersed nuclear elements), which belong to those retroposon families that have been preserved in vertebrate genomes for millions of years and are actively transcribed because they are embedded in the 3' untranslated region (UTR) of several genes. We report the results of the analysis of the genomic distribution of these mobile elements in zebrafish (Danio rerio) and discuss their involvement in generating miRNA gene loci. The computational study showed that the genes predicted to bear V-SINEs can be targeted by miRNAs with a very high hybridization E-value. Gene ontology analysis indicates that these genes are mainly involved in metabolic, membrane, and cytoplasmic signaling pathways. Nearly all the miRNAs that were predicted to target the V-SINEs of these genes, i.e., miR-338, miR-9, miR-181, miR-724, miR-735, and miR-204, have been validated in similar regulatory roles in mammals. The large number of genes bearing a V-SINE involved in metabolic and cellular processes suggests that V-SINEs may play a role in modulating cell responses to different stimuli and in preserving the metabolic balance during cell proliferation and differentiation. Although they need experimental validation, these preliminary results suggest that in the genome of D. rerio, as in other TE families in vertebrates, the preservation of V-SINE retroposons may also have been favored by their putative role in gene network modulation.