March issue cover: What’s going on here?

March

Alamy photo “Talus cones on Svalbard”

March is already winding to a close, but we wanted to take a quick break to answer that most burning of all questions: what is going on with our cover this month?

On p.331 of this month’s issue, Owen Rackham and colleagues describe an algorithm called Mogrify that predicts transcription factor combinations for direct reprogramming between 173 human cell types and 134 tissues (see also the News and Views by Patrick Cahan).

Mogrify effectively paints a landscape of cell conversions and provides directions for getting from one point to another. This is often visualized using a variation on Waddington’s epigenetic landscape (for example, see “A deterministic map of Waddington’s epigenetic landscape for cell fate specification” by Bhattacharya et al.).

Visualization of Waddington's epigenetic landscape

Visualization of Waddington’s epigenetic landscape{credit}Bhattacharya et al. BMC Syst Biol. 2011; 5: 85.{/credit}

The epigentic landscape as imagined by Waddington involves a marble (the cell) rolling down a hill with many alternate paths (cell fates).

You can imagine the image on the cover (depicting talus deposits on the surface of a mountain in Norway) as the epigenetic landscape, with the different cell fates rising out of the pluripotent state. In this case, there is no marble, because the cell and its fate (address on the landscape) are in fact the same thing. But similar to the talus cones, the cell’s fate is not unchangeable. As Mogrify makes clear, the cell has the potential to transform into many different cell types, regardless of its current address on the landscape. We just have to understand the map to help it get there.

Other articles related to Mogrify:

Breakthrough in human cell transformation could revolutionise regenerative medicine (University of Bristol press release)

Serendipity’s touch on cell conversions (Duke-NUS)

Genetic link between type 1 and type 2 diabetes

Dooley et al., Nature Genetics 2016

Dooley et al., Nature Genetics 2016

Type 1 and Type 2 diabetes (T1D and T2D) are complex diseases characterized by insulin signaling defects resulting from either autoimmune deregulation or metabolic dysfunction, respectively. Both cause disruption of blood glucose regulation and can lead to significant systemic effects. Despite the physiological distinctions underlying disease development, there are commonalities between T1D and T2D; in T1D, pancreatic beta cells are targeted by the autoimmune system, while in T2D there is gradual, progressive beta cell mass decline. There are some shared genetic risk factors associated with both conditions, but distinguishing between genetic versus secondary causes related to beta cell failure has been challenging.

A new study this week in Nature Genetics reports on a T1D model and the identification of genetic loci underlying beta cell fragility, independent of an immune component. TD1 non-obese diabetic (NOD) mice expressing the insHEL transgene, which causes unfolded protein stress, developed diabetes, and the authors determined that this was not dependent on adaptive immunity. They characterize mutations in two genes, Glis3 and Xrcc4, which compound the stress effects, leading to apoptosis. Changes in these molecular pathways are likewise reflected in islet cells of diabetes patients. This mouse model, therefore, could be useful in study possible targets to prevent beta cell loss. Continue reading

Bacterial methylomes and antibiotic potentiation

Cohen et al., Nature Genetics, 2016

Cohen et al., Nature Genetics, 2016

Antibiotics emerged as miracle drugs and “silver bullets” in the early 20th century, revolutionizing medicine and our ability to combat infectious disease while positively impacting health and lifespans on a large scale. This remarkable triumph held steady for many years, and consequently antibiotic research and development diminished as a priority due to the seeming defeat of bacterial infections. However, the selective pressure that came with antibiotic exposure led to the development of bacterial resistance to these compounds, motivating renewed interest in what is now an extremely important public health issue. Mechanisms of resistance are many and ever-evolving, and we know now that it is not a matter of IF bacteria will become resistant to a class of antibiotics, but when. The search for new and potentially exploitable bacterial vulnerabilities, then, becomes a constant enterprise in order for us to keep pace with the bacteria in the antibiotics/resistance arms race.

Cohen et al., Nature Genetics, 2016

Cohen et al., Nature Genetics, 2016

A new study this week in Nature Genetics describes how manipulating the bacterial DNA methylome affects susceptibility to multiple classes of antibiotics. The authors observed that deleting the dam gene, encoding a DNA methyltransferase, from E. coli causes increased susceptibility to sub-lethal doses of the β-lactam antibiotic ampicillin. Dam specifically methylates GATC sites, and deletion of any of the other three DNA methyltransferases found in E. coli had no effect on the level of antibiotic susceptibility. Using SMRT sequencing, the authors saw that genome-wide GATC methylation patterns did not change after exposure to ampicillin, so they sought alternative explanations for the observed phenotype. Continue reading

Human Genome Meeting 2016

I recently attended the Human Genome Meeting (HGM2016) in Houston, TX and wanted to share some of the highlights from the meeting.

The overall focus of the meeting was the application of genomics to medicine, and the presentations were, without exception, excellent. There is no way I can possibly summarize all of the great science that was presented at the meeting, but I’d like to focus on some general themes that emerged. Continue reading