Leading the Way in Life Science Technologies

GEN Exclusives

More »

GEN News Highlights

More »
October 29, 2014

Autoimmune Diseases Traced to Immune Cells Deranged by Epigenetic Aberrations

  • Genome-wide association studies of autoimmune disease have cataloged many, many gene variants, the significance of which has often proved elusive. Which gene variants are incidental, or neutral, and which are causative? And how might the causative variants actually bring harm?

    Questions such as these have been hard to answer because most DNA variants do not occur in protein-encoding genes. Instead, most variants lurk in noncoding regions of DNA. Here, variants such as single nucleotide polymorphisms (SNPs) readily defy explication. They might be stranded in stretches of “junk” DNA, or they might occupy strategic positions, influencing patterns of gene expression.

    Innocuous variants could be distinguished from potentially harmful variants if only they could be situated on a kind of map. In fact, such a map has been drawn by scientists from the University of California, San Francisco (UCSF), the Broad Institute, and Yale School of Medicine. These scientists assert that their map can pinpoint the complex genetic origins for numerous autoimmune diseases.

    The scientists started with a wealth of data from 39 genome-wide association studies. Then the scientists sifted through this data, which consisted of the genetic loci underlying 21 autoimmune diseases, with a new mathematical tool, a “fine-mapping algorithm.” It allowed them to generate predictions of which variants might be causal.

    Details of this work appeared October 29 in Nature, in an article entitled, “Genetic and epigenetic fine mapping of causal autoimmune disease variants.”

    “We integrated [causal variant] predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4+ T-cell subsets, regulatory T cells, CD8+ T cells, B cells, and monocytes,” wrote the authors. “We find that 90% of causal variants are noncoding, with 60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation.”

    In other words, the scientists found that most of the key DNA changes associated with autoimmune diseases occur in functional bits of DNA known as enhancers, regulatory sequences that can bind with proteins called transcription factors to enhance the expression of remotely located genes. Most of the enhancers identified in the Nature study did not correspond to DNA sequence motifs previously thought to be essential to enhancers, and had not previously been seen as having any functional role.

    “Compared to mutations that disrupt transcription factor motifs, alterations to noncanonical determinants may produce subtle but pivotal alterations to the immune response, without reaching a level of disruption that would result in strong negative selection,” the authors speculated. “Systematic integration of fine-mapped genetic and epigenetic data implies a nuanced complexity to disease variant function that will continue to push the limits of experimental and computational approaches.”

    “Once again, research is revealing new meaning in the world of DNA once thought of as junk—short, seemingly random DNA sequences that in fact serve meaningful roles in human physiology,” said Alex Marson, M.D., Ph.D., UCSF Sandler Faculty Fellow and the corresponding author for the study.

    Among other revelations, the new study strongly links the cause of multiple sclerosis (MS) to the immune system, not to genetic variants associated with the nervous system. According co-senior author David A. Hafler, M.D., professor of neurology and immunobiology and chair of the Department of Neurology at Yale, the study’s results provide definitive evidence that MS is an autoimmune disease, and that the immune system plays the primary role.

    “This is highly consistent with the new MS treatments that work on the immune system, suggesting that we finally have a good handle as to the underlying causes of MS,” said Dr. Hafler.

    The study also indicates it is possible to associate specific genetic variants with cell circuits that control gene activity and alter the physiology of specific immune cell types. This ability, notes Dr. Marson, could enable medical researchers to more precisely target therapeutic interventions in autoimmune diseases in order to dampen aberrantly fired-up immune responses.

    In his UCSF lab, Dr. Marson intends to probe more deeply how these newly identified DNA variants in enhancers affect cells, and how their disease-causing effects might be mitigated by DNA manipulations carried out using gene editing technologies such as CRISPR.

Related content

  • You’re all set! Thank you for subscribing to GEN Highlights.