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Title: Chromatin signature of widespread monoallelic expression}
Article:
Abstract:
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.
Introduction:
A variety of genetic and epigenetic factors affect the relative expression levels of the two copies of each given gene in diploid cells. In addition to cis- and trans-regulatory variation( Gilad et al., 2008), there are at least three major kinds of non-Mendelian phenomena that control allele-specific expression in mammals. One is the X chromosome inactivation( Lyon, 1961): in female embryos, around the time of implantation, about half of the cells choose to inactivate the maternal X, and the rest inactivate the paternal X, affecting most of the X-linked genes( Carrel and Willard, 2005; Berletch et al., 2010; Yang et al., 2010). Another is imprinting: genes such as IGF2 and H19 are expressed either from one allele, either paternal or maternal( Glaser et al., 2006). Finally, a significant fraction of mammalian autosomal genes are subject to monoallelic expression( MAE), which reflects a mitotically stable allele-specific expression with different allelic states in clonal lineages. MAE is observed in olfactory receptor genes( Chess et al., 1994), as well as genes coding for immunoglobulins and some cytokines( Pernis et al., 1965; Bix and Locksley, 1998; Holländer et al., 1998). Using genome-wide analyses of allele-specific expression, we and others have added a surprisingly large number of the autosomal genes in human and mouse to the MAE class( Gimelbrant et al., 2007; Jeffries et al., 2012; Zwemer et al., 2012; Li et al., 2012b), including genes implicated in a number of human diseases, such as Alzheimer’s disease( APP)( Bertram and Tanzi, 2012) and cancer( DAPK1)( Raval et al., 2007). MAE affects about 10% of ∼4000 tested genes in human lymphoblastoid cells( LCLs) and about 15% of more than 1300 assessed genes in analogous mouse cells( Gimelbrant et al., 2007; Zwemer et al., 2012). Our growing appreciation of the prevalence of MAE only underscores how little we know about its biology. The only existing, large-scale sets of data are collected in clonal lymphocyte cell lines in vitro. The limited number of analyzed clones is insufficient to generate a complete catalog of MAE genes in that cell type, and little is known about the prevalence of MAE in other cell types. Virtually nothing is understood about the establishment of MAE during development and differentiation. Mechanistically, allelic choice has been linked to changes in chromatin states in some special cases: imprinting( Wen et al., 2008), olfactory receptor gene choice( Magklara et al., 2011), and immunoglobulin-kappa gene rearrangement( Farago et al., 2012). In contrast, for hundreds of other autosomal MAE genes, no molecular features have been associated with establishment and maintenance of allelic choice. Similarly, there is no general understanding of MAE’s function. A major technical bottleneck in addressing these questions is the clonal nature of MAE( Figure1—figure supplement 1). Like X inactivation, MAE is masked in polyclonal samples, and obtaining monoclonal cell populations is challenging for most tissue types, particularly so in vivo. Moreover, genome-wide methods are limited by the availability of polymorphisms. In this study, we report a fundamentally new approach to the detection of monoallelic expression. In contrast to other methods, it does not require any allele-specific information, instead relying on a specific chromatin pattern as a proxy for MAE. We use this approach to address questions about MAE’s prevalence, development, and function.
Discussion:
Using a systematic machine learning approach, we identified and then experimentally validated a specific and sensitive signature for MAE: a gene-body overlap between chromatin marks for active transcription( H3K36me3) and gene silencing( H3K27me3). Interestingly, the promoter signal carried very little additional information relative to the gene-body features( Figure1—figure supplement 3). This could be due to some combination of biological reasons with much lower noise associated with gene body features due to their much greater length. It should also be noted that we focused on promoters and gene bodies because they are unequivocally associated with particular genes. It might be informative to study the involvement of other regulatory elements, such as enhancers. Upon applying this approach to a variety of cell types, we estimate that up to 20% of ubiquitously expressed genes and more than one-third of tissue-specific genes showed the chromatin signature of MAE. Since detection of the MAE signature does not rely on SNPs or on sample clonality, we expect that this approach will make feasible the analysis of MAE in primary samples, including systematic comparisons of normal and diseased tissue. Our findings fill three major gaps in our understanding of MAE. First, we have positively identified a molecular correlate of MAE with strong predictive power. We mapped MAE signature genome-wide in multiple cell types. Finally, we uncovered an unexpected relationship between MAE and known drivers of differentiation, bivalent genes, implying a functional role of MAE in this process. The overlap of MAE and bivalent genes poses a potential mechanistic puzzle. In the promoters of bivalent genes, both active and inactive modifications are simultaneously present on both alleles( Bernstein et al., 2006). Moreover, direct evidence showed individual nucleosomes carrying H3K4me3 or H3K36me3 along with H3K27me3, albeit on the opposite histone H3 tails( Voigt et al., 2012). At the same time, asymmetric distribution of H3K27me3 and H3K36me3 within the gene body of MAE genes is consistent with a very simple asymmetric model: H3K27me3 is known to be associated with transcriptionally silenced chromatin, and H3K36me3 is associated with gene bodies of the actively transcribed genes( Black et al., 2012). This leads us to speculate that transition of the bivalent genes from transcriptionally silent state with ‘poised’ chromatin into an active state often happens independently for the two alleles. In that scenario, either allele can become stably inactive, with gene body chromatin enriched with H3K27me3, while the other becomes active and enriched with H3K36me3( Figure 6B). Once the poised state has resolved into active or inactive state, it locks in that state; with some probability, both alleles become active, and the biallelic state is locked. While the molecular details of this process remain unclear, this model makes testable prediction that for bivalent genes, MAE is established during lineage commitment events, such as ES cell differentiation. Our finding of a specific combination of molecular markers associated with autosomal MAE creates opportunities for a deeper understanding of mechanisms underlying this epigenetic phenomenon. The presence of H3K27me3 immediately implies that histone methyltransferase EZH2, and possibly other components of the PRC2 complex( Margueron and Reinberg, 2011), could be involved in MAE maintenance. Our experimental observations suggest that H3K27me3 and H3K36me3 marks are asymmetrically distributed between the alleles of genes with MAE. Our observations are consistent with the idea that a uniform molecular mechanism might be involved in MAE maintenance genome-wide. Our study strongly implies that very similar sets of genes are subject to MAE in different individuals: the presence of the H3K36me3/H3K27me3 chromatin pattern in one individual corresponds to MAE in the same cell type in another individual. A parsimonious hypothesis is that the capacity for MAE is genetically controlled by regulatory DNA sequences, presumably in cis to the affected MAE genes. Consistent with this notion, significant inter-species conservation exists among genes subject to MAE in human and mouse( Zwemer et al., 2012). Epigenetic regulation of monoallelic expression can profoundly affect the relationship between genotype and molecular phenotype( Pereira et al., 2003; Zuo et al., 2007). One intriguing possibility is raised by a recent observation that genomically identical clones can be dramatically different in terms of tumorigenic properties and drug resistance( Kreso et al., 2012). The knowledge of the chromatin signature of MAE will help in exploring the relationship between MAE and functional cellular states in normal development and disease.
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 .