An epigenetic view of plant cells cultured in vitro: somaclonal variation and beyond

Epigenetic mechanisms are highly dynamic events that modulate gene expression. As more accurate and powerful tools for epigenetic analysis become available for application in a broader range of plant species, analysis of the epigenetic landscape of plant cell cultures may turn out to be crucial for understanding variant phenotypes. In vitro plant cell and tissue culture methodologies are important for many ongoing plant propagation and breeding programmes as well as for cutting-edge research in several plant model species. Although it has long been known that in vitro conditions induce variation at several levels, most studies using such conditions rely on the assumption that in vitro cultured plant cells/tissues mostly conform genotypically and phenotypically. However, when large-scale clonal propagation is the aim, there has been a concern in confirming true-to-typeness using molecular markers for evaluating stability. While in most reports genetic variation has been found to occur at relatively modest frequencies, variation in DNA methylation patterns seems to be much more frequent and in some cases it has been directly implicated in phenotypic variation. Recent advances in the field of epigenetics have uncovered highly dynamic mechanisms of chromatin remodelling occurring during cell dedifferentiation and differentiation processes on which in vitro adventitious plant regeneration systems are based. Here, an overview of recent findings related to developmental switches occurring during in vitro culture is presented. Additionally, an update on the detection of epigenetic variation in plant cell cultures will be provided and discussed in the light of recent progress in the plant epigenetics field.     

Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes

An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which suppresses tumorigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD1, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of ‘druggable’ targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify compounds that confer synthetic lethality with LIMD1 loss in NSCLC cells. PF-477736 was shown to selectively target LIMD1-deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 was effective in treating LIMD1^−/− tumours in subcutaneous xenograft models, with no significant effect in LIMD1^+/+ cells. We have identified a novel drug tool with significant preclinical characterisation that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.Subject terms: Targeted therapies, Non-small-cell lung cancer     

Implication of new atherosclerotic carotid plaques in the cardiovascular outcome of patients with rheumatoid arthritis

Early detection of atherosclerosis is of major importance to reduce the increased incidence of cardiovascular (CV) complications observed in patients with rheumatoid arthritis (RA). Prospective studies have shown that an abnormally increased carotid intima-media thickness and the presence of plaques assessed by carotid ultrasound are good markers to predict the development of CV events in these patients. Age, classic CV risk factors, and corticosteroid use are also predictors of new plaque formation in patients with RA. Active treatment of the disease may decrease the inflammatory burden, leading to a reduction in the progression of subclinical atherosclerosis in these patients.     

Masting uncoupling: mast seeding does not follow all mast flowering episodes in a dioecious juniper tree

Evolutionary selective forces, like predator satiation and pollination efficiency, are acknowledged to be major causes of masting (the variable, periodic and synchronic production of seeds in a population). However, a number of recent studies indicate that resources might also play an important role on shaping masting patterns. Dioecious masting species offer a privileged framework to study the role of resources on masting variation, since male and female plants often experience different reproductive costs and selective pressures. We followed masting and reproductive investment (RI) of the dioecious tree Juniperus thurifera in two populations along 10 years and studied the different response of males and females to experimentally increased water and nutrient availability in a third population. Juniperus thurifera females invested in reproduction three times more resources than males. Such disparity generated different resource‐use strategies in male and female trees. Tree‐ring growth and water use efficiency (WUE) confirmed that sexes differed in their resource investment temporal pattern, with males using current resources for reproduction and females using resources accumulated during longer periods. Watered and fertilized female trees presented significantly higher flowering reproductive investments than males and experienced an extraordinary mast‐flowering event. However, seeding RI and mast seeding were not affected by the treatment. This suggests that although resource availability affects the reproductive output of this species, there are other major forces regulating masting on J. thurifera. During 10 years, J. thurifera male and female trees presented high and low flowering years more or less synchronously. However, not all mast flowering episodes resulted in mast seeding, leading to masting uncoupling between flowering and seeding. Since flowering costs represent only 1% of females’ total reproductive investments, masting uncoupling could be a beneficial bet‐hedging strategy to maximize reproductive output in spite of unpredictable catastrophic events.