Adam Mark

High-performance web services for querying gene and variant annotation

Efficient tools for data management and integration are essential for many aspects of high-throughput biology. In particular, annotations of genes and human genetic variants are commonly used but highly fragmented across many resources. Here, we describe MyGene.info and MyVariant.info, high-performance web services for querying gene and variant annotation information. These web services are currently accessed more than three million times per month. They also demonstrate a generalizable cloud-based model for organizing and querying biological annotation information. MyGene.info and MyVariant.info are provided as high-performance web services, accessible at http://mygene.info and http://myvariant.info. Both are offered free of charge to the research community.

A Structurally Distinct Human Mycoplasma Protein that Generically Blocks Antigen-Antibody Union

Easy M Our immune systems can produce a vastly diverse repertoire of antibody molecules that each recognize and bind to a specific foreign antigen via a hypervariable region. However, there are a few bacterial antigens—such as Protein A, Protein G, and Protein L—that instead bind to the antibodys conserved regions and can bind to a large number of different antibodies. These high-affinity broad-spectrum antibody-binding properties have been widely exploited both in the laboratory and in industry for purifying, immobilizing, and detecting antibodies. Grover et al. (p. 656) have now identified Protein M found on the surface of human mycoplasma, which displays even broader antibody-binding specificity. The crystal structure of Protein M revealed how Protein-M binding blocks the antibodys antigen binding site. This mechanism may be exploited by mycoplasma to escape the humoral immune response. High-affinity binding of Protein M to a very broad range of human antibodies may find widespread immunochemical applications. We report the discovery of a broadly reactive antibody-binding protein (Protein M) from human mycoplasma. The crystal structure of the ectodomain of transmembrane Protein M differs from other known protein structures, as does its mechanism of antibody binding. Protein M binds with high affinity to all types of human and nonhuman immunoglobulin G, predominantly through attachment to the conserved portions of the variable region of the κ and λ light chains. Protein M blocks antibody-antigen union, likely because of its large C-terminal domain extending over the antibody-combining site, blocking entry to large antigens. Similar to the other immunoglobulin-binding proteins such as Protein A, Protein M as well as its orthologs in other Mycoplasma species could become invaluable reagents in the antibody field.

H3K27 Methylation Dynamics during CD4 T Cell Activation: Regulation of JAK/STAT and IL12RB2 Expression by JMJD3

The changes to the epigenetic landscape in response to Ag during CD4 T cell activation have not been well characterized. Although CD4 T cell subsets have been mapped globally for numerous epigenetic marks, little has been done to study their dynamics early after activation. We have studied changes to promoter H3K27me3 during activation of human naive and memory CD4 T cells. Our results show that these changes occur relatively early (1 d) after activation of naive and memory cells and that demethylation is the predominant change to H3K27me3 at this time point, reinforcing high expression of target genes. Additionally, inhibition of the H3K27 demethylase JMJD3 in naive CD4 T cells demonstrates how critically important molecules required for T cell differentiation, such as JAK2 and IL12RB2, are regulated by H3K27me3. Our results show that H3K27me3 is a dynamic and important epigenetic modification during CD4 T cell activation and that JMJD3-driven H3K27 demethylation is critical for CD4 T cell function.

MyGene.info: gene annotation query as a service

Biomedical knowledge is often represented as annotations of biological entities such as genes, genetic variants, diseases, and drugs. For gene annotations, they are fragmented across data repositories like NCBI Entrez, Ensembl, UniProt, and hundreds (or more) of other specialized databases. While the volume and breadth of annotations is valuable, their fragmentation across many data silos is often frustrating and inefficient. Bioinformaticians everywhere must continuously and repetitively engage in data wrangling in an effort to comprehensively integrate knowledge from all these resources, and these uncoordinated efforts represent an enormous duplication of work. We previously released MyGene.info (http://mygene.info) to enable bioinformatics developers to gain programmatic access to gene annotation data through our high-performance web services. This article focuses on the updates to MyGene.info since our last paper (2013 database issue). With the completely re-factored system, MyGene.info now expands the support from the original nine species to over 14K species, covering >17M genes with >50 gene-specific annotation types. Two simple web service endpoints provides high-performance query access to all these aggregated gene annotations. The infrastructure underlying MyGene.info is highly scalable, which offers both high-performance and high-concurrency, and makes MyGene.info particularly suitable for the use cases of real-time applications and analysis pipelines.

Promoter H3K4 methylation dynamically reinforces activation-induced pathways in human CD4 T cells

The epigenetic determinants driving the responses of CD4 T cells to antigen are currently an area of active research. Much has been done to characterize helper T-cell subsets and their associated genome-wide epigenetic patterns. In contrast, little is known about the dynamics of histone modifications during CD4 T-cell activation and the differential kinetics of these epigenetic marks between naive and memory T cells. In this study, we have detailed the dynamics of genome-wide promoter H3K4me2 and H3K4me3 over a time course during activation of human naive and memory CD4 T cells. Our results demonstrate that changes to H3K4 methylation occur relatively late after activation (5 days) and reinforce activation-induced upregulation of gene expression, affecting multiple pathways important to T-cell activation, differentiation and function. The dynamics and mapped pathways of H3K4 methylation are distinctly different in memory cells, which have substantially more promoters marked by H3K4me3 alone, reinforcing their more differentiated state. Our study provides the first data examining genome-wide histone modification dynamics during CD4 T-cell activation, providing insight into the cross talk between H3K4 methylation and gene expression, and underscoring the impact of these marks upon key pathways integral to CD4 T-cell activation and function.

MyGene.info and MyVariant.info: Gene and Variant Annotation Query Services

MyGene.info and MyVariant.info provide high-performance data APIs for querying gene and variant annotation information. They demonstrate a new model for organizing biological annotation information by utilizing a cloud-based scalable infrastructure. MyGene.info and MyVariant.info can be accessed at http://mygene.info and http://myvariant.info.