Science: genetic variation of enhancer in brain cell type or prediction of disease risk

November 21, 2019 news / Biovalley BIOON / - -- it may be thought that the main cause of most genetic related diseases comes from mutations in the coding DNA --- changes in the coding region of the genome can directly lead to changes in the expression of specific proteins important to healthy human body However, most of human DNA is noncoding DNA, that is, DNA regions that do not directly translate functional proteins These noncoding DNA regions contain regulatory sequence elements called enhancers, which can change the probability that specific proteins are made In a new study, researchers from the University of California, San Diego School of medicine and the shack Institute of biology and other research institutions now find specific genetic variations in some enhancers that determine whether proteins are expressed in specific cell types in the brain and may play a role in people's risk of mental or neurological disease Using healthy tissue extracted from six patients, they isolated four different types of brain cells - neurons, microglia, oligodendrocytes and astrocytes Then they studied the genetic variation related to disease in enhancers of each cell type to find the variation possibly related to disease risk The related research results were published online in the journal Science on November 14, 2019 The paper title is "brain cell type – specific enhancer promoter interface maps and disease risk association" The picture is from cc0 public domain By using new molecular technology, they can further determine the relationship between enhancer regions and their target genes, thus providing new insights on how the variation of enhancer regions affects the expression of downstream genes in specific cell types "The brain is very complex and there are many different cell types in different brain regions," said Dr Inge holtman, CO lead author of the paper and a postdoctoral researcher in the Department of cell and molecular medicine at the University of California, San Diego School of medicine At present, our understanding of regulatory landscape is still largely unknown Previous studies have tried to create a consistent regulatory picture of the whole brain, but until now we have not really understood what it looks like in a single cell type This study gives us a better understanding of how genes are regulated, which enhancers exist, and which enhancers loop back to specific genes and affect their expression, especially the specific cell types in the brain " These results show that although many genes are expressed in many different cell types, enhancer regions differ from cell to cell, and disease risk is usually related to specific enhancer regions in specific cell types "Looking at the genetic variation associated with Alzheimer's disease (AD), we found that the disease risk variation is preferentially concentrated in the enhancers with selective activity in microglia (the main immune cells in the brain)," said Christopher glass, Ph.D., pH This finding greatly extends previous studies that have linked microglia to advanced Alzheimer's disease " In addition to identifying genetic risk variants, the researchers validated their findings with human pluripotent stem cells By targeting a specific enhancer region near the Bin1 gene, which has previously been linked to Alzheimer's disease, they found that removing this enhancer region resulted in a significant decrease in Bin1 expression in microglia rather than neurons or astrocytes, suggesting that Bin1 The related risk alleles are located in the microglial specific enhancer region Dr Nicole coufall, CO lead author of the paper and part-time assistant professor of pediatrics at the University of California, San Diego School of medicine, said: "it is often difficult to know which cell types specific genes are important, because they may be expressed in all cell types of the brain In Alzheimer's disease, Bin1 was previously thought to be the most important in neurons, but this study suggests that understanding the role of Bin1 in microglia may actually be more important " The researchers say their findings will help inform future research into genetic risk variation in many different neurological diseases "In the near future, this study will provide new targets and tell us about the cells to be studied," said Dr Alexi nott, CO lead author of the paper and assistant project scientist in the Department of cell and molecular medicine at the University of California, San Diego School of medicine Looking to the future, our data set can be used by others interested in studying many different brain diseases " Nott said the researchers plan to continue using the method to generate more research targets "Given that we are looking at healthy tissue, we may lack some regulatory areas that play an important role in disease It is possible that some of these regulatory sequence elements change only in the disease We also hope to study more cell types But this study is a great starting point for us to further understand how important these cell-specific regulatory regions may be for understanding disease risk " (bio Com) reference: 1 Alexi nott et al Brain cell type – specific enhancer promoter interaction maps and disease risk association Science, 2019, doi:10.1126/science.aay0793 2.Genetic variation in individual brain cell types may predict disease risk https://medicalxpress.com/news/2019-11-genetic-variation-individual-brain-cell.html