April 2017

Induced pluripotent stem cell differentiation enables functional validation of GWAS variants in metabolic disease

This study was focused on the effect of common genetic variants on liver cell function. We used a cocktail of proteins to reprogram blood cells from participants of the Framingham Heart Study into stem cells. These stem cells were differentiated into millions of liver and fat cells in the lab to investigate how the genome of each FHS participant affected cellular functions related to heart disease. We discovered a correlation between one common genetic variant and lipid accumulation in liver cells. Our results point toward an emerging methodology in human population genetics: stem cell-driven investigations into the correlation between common genetic variants and cellular functions.

Summary provided by Chad Cowan, PhD, of the Center for Regenerative Medicine at Massachusetts General Hospital, and senior author of the study.

Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors

Suspecting that the handful of known subtypes of dendritic cells and related cells (known as monocytes) overlooked important differences between cells, a team of scientists at the Broad Institute of MIT and Harvard recently took an unbiased survey of this family of cells, with the goal of revealing how the immune response works in disease. Using single-cell genomic approaches, the researchers analyzed gene expression patterns of individual human blood cells and performed functional validation to revise the classification of these cells, uncovering dendritic cell ancestors in the blood and a new cell subtype that may have therapeutic implications. Appearing in the April 21 issue of Science, the study highlights the value of embarking on a comprehensive Human Cell Atlas initiative, which the international community is now taking on, and it offers a useful framework for conducting this kind of analysis on other cell types and tissues.

Summary provided by Nir Hacohen, PhD, co-director of the Cell Circuits Program and an institute member at the Broad Institute of MIT and Harvard, director of the Massachusetts General Hospital Center for Cancer Immunology, and an associate professor of medicine at Harvard Medical School, and co-senior author of the study.

DUSP9 modulates DNA hypomethylation in female mouse pluripotent stem cells

Pluripotent stem cells are master cells that hold great promise in regenerative medicine because of their potential to produce any cell or tissue the body needs to repair itself. Previous research suggested that two commonly used types of pluripotent stem cells, embryonic stem cells and embryonic germ cells, are fundamentally different at the level of DNA methylation, a crucial regulatory DNA modification that controls the activity of thousands of genes. Scientists were led to believe that the molecular differences between these two cell types originated from their different origins, embryos or germ cells. Here, Choi, Hochedlinger and colleagues revisited this historic observation by conducting a careful side-by-side comparison of DNA methylation patterns between genetically matched embryonic stem cells and embryonic germ cells. The authors observed that most of the variation in DNA methylation patterns between the two cell types derives from the sex of the cell lines rather than their origin, with female stem cells being generally less methylated than male stem cells. The authors discovered that this female-specific undermethylation is due to the upregulation of the gene DUSP9, which is located on the X chromosome and thus present in two copies in female cells. These results underscore profound sex-specific molecular differences in pluripotent stem cells, which has implications for gene regulation studies and potentially therapeutic applications.

Summary provided by Konrad Hochedlinger, PhD, of the Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine at Massachusetts General Hospital, and senior author of the study.

Delays in emergency care and mortality during major U.S. marathons

Marathons and other large public events involve road closures that may make it difficult for ambulances to transport patients to the hospital. Analyzing data from 11 U.S. cities that hosted major marathons during 2002-2011, we found that for every 100 individuals who experience an acute cardiac event, an additional 4 would die within 1 month if the cardiac event occurred on the day of a marathon compared to the surrounding weeks. We also found that the time it takes ambulances to transport patients to the hospital increased by nearly 30% on marathon days. These findings suggest that city planners and organizers of large public events should be aware of care delays that may arise due to road closures and other infrastructure disruptions. In addition, the public should be aware of potential delays; individuals who experience medical emergencies should not attempt to drive themselves to the hospital during large public events, but should instead call 9-1-1.

Summary provided by Anupam B. Jena, MD, PhD, a physician in the Department of Medicine at Massachusetts General Hospital, and lead author of the study.

Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity

The human genome project provided a 'parts-list' of genes, about 18,000 in number. Now, researchers are studying what it means to be missing a part. In an analysis of the genomes of 10,000 research participants, Dr. Sekar Kathiresan and his research team at MGH and the Broad Institute found 1,300 genes which were broken in at least one participant. For example, several individuals were missing a working copy of the APOC3 gene and as a result, these individuals had lower blood levels of fat and were protected from heart attack. Such examples help us understand the function of a gene in humans and also point to new drug targets. This study sets the stage for an ambitious ‘Human Knockout Project’, a systematic effort to understand gene function by identifying and characterizing humans who naturally lack a gene.

Summary provided by Sekar Kathiresan, MD, the Director of the Center for Genomic Medicine at Massachusetts General Hospital, and senior author of the study.

Macrophages facilitate electrical conduction in the heart

While we knew for a while that the healthy heart contains tissue resident macrophages, these cells’ organ specific functions were unknown. Triggered by a serendipitous finding of ECG abnormalities during a cardiac MRI scan of a mouse after macrophage ablation, a team of investigators from Mass General's Center for Systems Biology now describes previously unknown electrical properties of macrophages. When coupled to myocytes via gap junctions, macrophages depolarize in sync with conducting cells. In a sink-source relationship, electric current flows back and forth between macrophages and cardiomyocytes. Macrophages influence conduction through the atrioventricular node, the electrical connection between the heart’s chambers. When macrophages are manipulated, the flow of electricity slows down, and may even cease altogether. Such a condition requires pacemaker treatment in humans. These surprising findings, published in Cell, jolt the field of electrophysiology and may lead to new therapeutic opportunities for patients with cardiac arrhythmias. The collaborative effort was spearheaded by teams at MGH but also involved investigators at the BWH and in Freiburg, Germany.

Summary provided by Matthias Nahrendorf, MD, PhD, Director of the Mouse Imaging Program at the Center for Systems Biology at Massachusetts General Hospital, and senior author of the study.

Phenome-wide heritability analysis of the UK Biobank

Heritability — the proportion of individual differences in a trait that can be explained by individual differences in DNA — provides fundamental information about the genetic basis of diseases and the prospects for genetic risk prediction. Most human traits and diseases are heritable, but the levels of heritability vary and can be affected by environmental factors. In this study, Tian Ge, Jordan Smoller, and MGH colleagues developed powerful new methods to estimate the heritability of more than 550 traits and diseases using genomic data for 150,000 individuals in the population-based UK Biobank. They also demonstrate how age, sex and socioeconomic status can affect heritability, providing the most comprehensive characterization of the contribution of genetic variation to human complex traits.

Summary provided by Tian Ge, PhD, Research Fellow at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital, and lead author.Jordan Smoller, PhD, director of the Psychiatric and Neurodevelopmental Genetics Unit in Mass General's Center for Human Genetics Research, is senior author of the study.

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