The Impact of Local Genome Sequence on Defining Heterochromatin Domains

Characterizing how genomic sequence interacts with trans-acting regulatory factors to implement a program of gene expression in eukaryotic organisms is critical to understanding genome function. One means by which patterns of gene expression are achieved is through the differential packaging of DNA into distinct types of chromatin. While chromatin state exerts a major influence on gene expression, the extent to which cis-acting DNA sequences contribute to the specification of chromatin state remains incompletely understood. To address this, we have used a fission yeast sequence element (L5), known to be sufficient to nucleate heterochromatin, to establish de novo heterochromatin domains in the Schizosaccharomyces pombe genome. The resulting heterochromatin domains were queried for the presence of H3K9 di-methylation and Swi6p, both hallmarks of heterochromatin, and for levels of gene expression. We describe a major effect of genomic sequences in determining the size and extent of such de novo heterochromatin domains. Heterochromatin spreading is antagonized by the presence of genes, in a manner that can occur independent of strength of transcription. Increasing the dosage of Swi6p results in increased heterochromatin proximal to the L5 element, but does not result in an expansion of the heterochromatin domain, suggesting that in this context genomic effects are dominant over trans effects. Finally, we show that the ratio of Swi6p to H3K9 di-methylation is sequence-dependent and correlates with the extent of gene repression. Taken together, these data demonstrate that the sequence content of a genomic region plays a significant role in shaping its response to encroaching heterochromatin and suggest a role of DNA sequence in specifying chromatin state

Area-level socioeconomic characteristics and incidence of metabolic syndrome: a prospective cohort study

BACKGROUND The evidence linking socioeconomic environments and metabolic syndrome (MetS) has primarily been based on cross-sectional studies. This study prospectively examined the relationships between area-level socioeconomic position (SEP) and the incidence of MetS. METHODS A prospective cohort study design was employed involving 1,877 men and women aged 18+ living in metropolitan Adelaide, Australia, all free of MetS at baseline. Area-level SEP measures, derived from Census data, included proportion of residents completing a university education, and median household weekly income. MetS, defined according to International Diabetes Federation, was ascertained after an average of 3.6 years follow up. Associations between each area-level SEP measure and incident MetS were examined by Poisson regression Generalised Estimating Equations models. Interaction between area- and individual-level SEP variables was also tested. RESULTS A total of 156 men (18.7%) and 153 women (13.1%) developed MetS. Each percentage increase in the proportion of residents with a university education corresponded to a 2% lower risk of developing MetS (age and sex-adjusted incidence risk ratio (RR) = 0.98; 95% confidence interval (CI) =0.97-0.99). This association persisted after adjustment for individual-level income, education, and health behaviours. There was no significant association between area-level income and incident MetS overall. For the high income participants, however, a one standard deviation increase in median household weekly income was associated with a 29% higher risk of developing MetS (Adjusted RR = 1.29; 95%CI = 1.04-1.60). CONCLUSIONS While area-level education was independently and inversely associated with the risk of developing MetS, the association between area-level income and the MetS incidence was modified by individual-level income.Anh D Ngo, Catherine Paquet, Natasha J Howard, Neil T Coffee, Robert Adams, Anne Taylor and Mark Danie

Targeting Colon Cancers with Mutated BRAF and Microsatellite Instability

The subgroup of colon cancer (CRC) characterized by mutation in the BRAF gene and high mutation rate in the genomic DNA sequence, known as the microsatellite instability (MSI) phenotype, accounts for roughly 10% of the patients and derives from polyps with a serrated morphology. In this review, both features are discussed with regard to therapeutic opportunities. The most prevalent cancer-associated BRAF mutation is BRAF V600E that causes constitutive activation of the pro-proliferative MAPK pathway. Unfortunately, the available BRAF-specific inhibitors had little clinical benefit for metastatic CRC patients due to adaptive MAPK reactivation. Recent contributions for the development of new combination therapy approaches to pathway inhibition will be highlighted. In addition, we review the promising role of the recently developed immune checkpoint therapy for the treatment of this CRC subtype. The MSI phenotype of this subgroup results from an inactivated DNA mismatch repair system and leads to frameshift mutations with translation of new amino acid stretches and the generation of neo-antigens. This most likely explains the observed high degree of infiltration by tumour-associated lymphocytes. As cytotoxic lymphocytes are already part of the tumour environment, their activation by immune checkpoint therapy approaches is highly promising.info:eu-repo/semantics/publishedVersio