Chromatin signature of widespread monoallelic expression.
Chromatin signature of widespread monoallelic expression.
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DOI：
10.7554/elife.01256
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发表时间：
2013-12-31
期刊：
影响因子：
7.7
通讯作者：
Gimelbrant AA
中科院分区：
文献类型：
--
作者：
Nag A;Savova V;Fung HL;Miron A;Yuan GC;Zhang K;Gimelbrant AA
In mammals, numerous autosomal genes are subject to mitotically stable monoallelic expression (MAE), including genes that play critical roles in a variety of human diseases. Due to challenges posed by the clonal nature of MAE, very little is known about its regulation; in particular, no molecular features have been specifically linked to MAE. In this study, we report an approach that distinguishes MAE genes in human cells with great accuracy: a chromatin signature consisting of chromatin marks associated with active transcription (H3K36me3) and silencing (H3K27me3) simultaneously occurring in the gene body. The MAE signature is present in ∼20% of ubiquitously expressed genes and over 30% of tissue-specific genes across cell types. Notably, it is enriched among key developmental genes that have bivalent chromatin structure in pluripotent cells. Our results open a new approach to the study of MAE that is independent of polymorphisms, and suggest that MAE is linked to cell differentiation. DOI: http://dx.doi.org/10.7554/eLife.01256.001 Understanding how genes are activated and silenced is one of the central challenges in modern biology. These processes underpin the development of a fertilized egg into a complex organism, and they can also lead to life-threatening diseases when they go wrong. There are two copies of each gene in a human cell, a maternal copy and a paternal copy, and it is thought that both copies are usually regulated together. However, there are exceptions to this rule: for certain genes only the maternal copy is expressed as a protein in some cells, whereas the paternal copy is expressed in other cells. This form of gene regulation, which is called monoallelic expression, can result in neighboring cells heading down very different paths. In extreme cases, depending on the differences between the two copies of the gene, cells that express one copy may function normally, while cells where the other copy is activated will start forming tumors. However, despite these potentially grave consequences, and early results which suggested that monoallelic expression affected a large number of human and mouse genes, it has proved to be a major technical challenge to identify these genes in most cell types. Now, Nag, Savova et al. have discovered a molecular signature that can be used to detect monoallelic expression. The signature was found in chromatin, the densely packed structure formed by DNA and proteins inside the cell nucleus. Nag, Savova et al. discovered that the genes that are subject to monoallelic expression are bound with proteins that are modified in two contrasting ways. One modification, which is usually a sign of gene silencing, is prevalent on the inactive copy of the gene, and the other, which often marks active genes, is chiefly present on the active copy. Nag, Savova et al. report that these modifications are found in different sets of genes in different cell types, indicating distinct genome-wide patterns of monoallelic expression. The chromatin signature approach lets them estimate the fraction of human genes that are subject to monoallelic expression. This number is surprisingly high: about 20% of commonly expressed genes and more than one-third of tissue-specific genes. In a particularly intriguing finding, almost all bivalent genes—a subset of genes that are involved in determining the fate of cell during development—are estimated to become monoallelic when they are activated. In addition to these unexpected findings, the chromatin signature approach opens the door to exploring monoallelic expression as a form of gene regulation in all types of cells and, ultimately, to understanding how it is involved in both normal development and in disease. DOI: http://dx.doi.org/10.7554/eLife.01256.002
