Nature & Nature++
The implications of this Nature paper from last week are major for the stem cell community: Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations (Merkle et al. 2017).
Nature Genetics: Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci (Stender et al. 2017)
Nature Genetics: Pathogenic variants that alter protein code often disrupt splicing (Soemedi et al. 2017). Copied from abstract: “We analyzed 4,964 published disease-causing exonic mutations using a massively parallel splicing assay (MaPSy), which showed an 81% concordance rate with splicing in patient tissue. Approximately 10% of exonic mutations altered splicing, mostly by disrupting multiple stages of spliceosome assembly. We present a large-scale characterization of exonic splicing mutations using a new technology that facilitates variant classification and keeps pace with variant discovery.” I can’t even imagine how expensive this study must have been…
Nature Reviews Endocrinology: Metric for glycaemic control – from HbA2c to continuous glucose monitoring. Copied from abstract so you can decide if relevant or not: “I focus on markers of average glycaemia and the utility and/or shortcomings of HbA1c as a ‘gold-standard’ metric of glycaemic control; the notion that glucose variability is characterized by two principal dimensions, amplitude and time; measures of glucose variability that are based on either self-monitoring of blood glucose data or continuous glucose monitoring (CGM); and the control of average glycaemia and glucose variability through the use of pharmacological agents or closed-loop control systems commonly referred to as the ‘artificial pancreas’. I conclude that HbA1c and the various available metrics of glucose variability reflect the management of diabetes mellitus on different timescales, ranging from months (for HbA1c) to minutes (for CGM).”
Nature Cell Biology: Cell Competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes (Kon et al. 2017). This very interesting for the benign-malignant paradox that refers to the occurrence of cancerous mutations in benign disease without further progression to cancer. Here is a copy of the abstract (I read the paper, and it seems solid experimentally although they perform all the wrong statistics throughout!!): “Recent studies have revealed that newly emerging transformed cells are often apically extruded from epithelial tissues. During this process, normal epithelial cells can recognize and actively eliminate transformed cells, a process called epithelial defence against cancer (EDAC). Here, we show that mitochondrial membrane potential is diminished in RasV12-transformed cells when they are surrounded by normal cells. In addition, glucose uptake is elevated, leading to higher lactate production. The mitochondrial dysfunction is driven by upregulation of pyruvate dehydrogenase kinase 4 (PDK4), which positively regulates elimination of RasV12-transformed cells. Furthermore, EDAC from the surrounding normal cells, involving filamin, drives the Warburg-effect-like metabolic alteration. Moreover, using a cell-competition mouse model, we demonstrate that PDK-mediated metabolic changes promote the elimination of RasV12-transformed cells from intestinal epithelia. These data indicate that non-cell-autonomous metabolic modulation is a crucial regulator for cell competition, shedding light on the unexplored events at the initial stage of carcinogenesis.” There is a news & and views as well: “Metabolic changes promote rejection of oncogenic cells.”
Nature Cell Biology: Metabolic control of primed human pluripotent stem cell fate and function by the miR-200c-SIRT2 axis (Cha et al. 2017). After a quick skim, seems OK overall, except that I don’t trust the qPCR results because of the way they are represented. Would be great if people could stop normalising to samples where a gene is not expressed anyway (we have all been taught basic maths and know that you can’t divide by 0)… Not an attack on this study only, but on most qPCR studies these days. There is also a news&views on this paper in Nature Cell Biology as well (SIRT2 and glycolytic enzyme acetylation in pluripotent stem cells). What is interesting, though, is this whole concept of a glycolytic-acetyl-coA switch that could interact with the epigenetics of stem cells and their cell fate decisions.
Nature Cell Biology: SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis. Can’t actually access the actual article 😦 It says aop, not sure what it means, though.
For those of us with a sweet tooth (a pathological tendency to snack!!), FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans (Søberg, Sandholt et al. 2017). The gist of it is that there are human genetic variants in FGF21 that increase sweet preference, but surprisingly they do not correlate with obesity/diabetes. I found some of the points in the Introduction interesting – those regarding the difference between mouse and human FGF21 biology. So a word of caution when it comes to metabolism and species-specific differences!
From the Japanese iPSCs experts on the effect of metabolism on pluripotency states, published in Cell Metabolism: Hybrid Cellular Metabolism Coordinated by Zic3 and Esrrb Synergistically Enhances Induction of Naive Pluripotency (Sone et al. 2017). Currently, a hot topic in the stem cell field is the notion of naive vs primed pluripotency. Human iPSCs and ESCs are thought to be “primed”, i.e. more lineage-restricted and corresponding to the post-implantation epiblast state, compared to mouse counterparts which correspond to pre-implantation embryonic cells. Mouse ESCs can be induced to become even more naive (so can human ESCs/iPSCs as of recently) with certain small molecules or by genetic perturbation. Interestingly, whereas more primed stem cells rely on glycolysis, and low rates of oxidative phosphorylation, naive pluripotency seems to require both glycolysis and oxidative phosphorylation. This balance is now shown to depend on the synergy between the transcription factors Zic3 and Esrrb which both activate glycolysis genes, but have opposite effects on OXPHOS. It is really interesting to follow the metabolic theme in stem cells – the ability of cells to shift their metabolism is emerging as an important prerequisite for appropriate cell fate regulation. Also, although this study determines that both glycolysis and OXPHOS need to be ON for efficient reprogramming of mouse fibroblasts to naive stem cells, it still doesn’t have the answer as to why this is the case. Technically, this study is also quite neat – done well! Although quite interesting to see raw Ct values being reported as opposed to log-transformed derivatives (BUT great that the spread of the data is shown properly and SDs are used!).
A review on “Autophagy and Tumour Metabolism” (Kimmelman & White, 2017) ➡ interesting, examining both cell-autonomous and non-cell-autonomous effects. This field is also seeing a shift in perception, recognising that autophagy may be tumour-suppressive at the early stages of tumour initiation, but promote tumour growth at later stages (possibly due to systemic interactions of the cancer with non-cancerous tissues).
A review of “Metabolic Flexibility in Health and Disease” (Goodpaster & Sparks, 2017) that will interest quite a few people as it examines fasting/refeeding paradigms and emphasises the role of skeletal muscle and adipose tissue. It also briefly examines evidence for and against the importance of individual tissues for the development of insulin resistance.