Search

Chronic inflammatory diseases (CIDs) have complex pathologies that result from aberrant and persistent immune responses. However, the precise triggers and mechanisms remain elusive. An important aspect of CID research focuses on epigenetics modifications, which regulate gene expression and provide a dynamic transcriptional response to inflammation. In recent years, mounting evidence has demonstrated an association between epigenomic and transcriptomic dysregulation and the phenotypes of CIDs. In particular, epigenetic changes at cis-regulatory elements have provided new insights for immune cell-specific alterations that contribute to disease etiology. Furthermore, the advancements in single-cell genomics provide novel solutions to cell type heterogeneity, which has long posed challenges for CID diagnosis and treatment. In this review, we discuss the current state of epigenomics research of CID and the insights derived from single-cell transcriptomic and epigenomic studies.

Gene expression is regulated by a large variety of mechanisms. Previous studies attempting to model the quantitative relationships between gene expression levels and regulatory mechanisms have considered only one or a few mechanisms at a time, which cannot provide a full picture of the complex interactions among different mechanisms. This was partially due to the heterogeneity of the mechanisms, which involve different types of biological objects and data representations, making it hard to study them in a unified way. Here, we describe a flexible framework that can integrate very different types of data for studying their joint effects on gene expression. In this framework, domain knowledge is represented by metapaths, while the manifestations of their effects in actual data are summarized by an embedding of the biological objects in a latent space. We demonstrate the use of our framework in integrating several diverse types of data that are related to gene expression in different ways, including DNA contacts in three-dimensional genome architecture, protein–protein interactions, genomic neighbourhoods and broad chromatin accessibility domains. The modelling results reveal that these several types of data are able to model gene expression fairly well individually, but even better when integrated. Gene expression is regulated by a variety of mechanisms, which have been difficult to study in a unified way. The authors propose a flexible framework that can integrate different types of data for studying their joint effects on gene expression. The framework uses a general network representation for data integration, metapaths for inputting prior knowledge of gene regulatory mechanisms, and embedding techniques for capturing complex structures in the data.

Polymorphic integrations of endogenous retroviruses (ERVs) have been previously detected in mouse and human genomes. While most are inert, a subset can influence the activity of the host genes. However, the molecular mechanism underlying how such elements affect the epigenome and transcriptome and their roles in driving intra-specific variation remain unclear. Here, by utilizing wildtype murine embryonic stem cells (mESCs) derived from distinct genetic backgrounds, we discover a polymorphic MMERGLN (GLN) element capable of regulating H3K27ac enrichment and transcription of neighboring loci. We demonstrate that this polymorphic element can enhance the neighboring Klhdc4 gene expression in cis, which alters the activity of downstream stress response genes. These results suggest that the polymorphic ERV-derived cis-regulatory element contributes to differential phenotypes from stimuli between mouse strains. Moreover, we identify thousands of potential polymorphic ERVs in mESCs, a subset of which show an association between proviral activity and nearby chromatin states and transcription. Overall, our findings elucidate the mechanism of how polymorphic ERVs can shape the epigenome and transcriptional networks that give rise to phenotypic divergence between individuals., How polymorphic elements can drive intra-species variation has not been clearly examined. Here the authors show that the polymorphic GLN endogenous retrovirus (ERV) functions as a cis-regulatory element for neighboring genes, leading to differences in how two mouse strains respond to stress.

The Origin Recognition Complex (ORC) is an evolutionarily conserved six-subunit protein complex that binds specific sites at many locations to coordinately replicate the entire eukaryote genome. Though highly conserved in structure, ORC’s selectivity for replication origins has diverged tremendously between yeasts and humans to adapt to vastly different life cycles. In this work, we demonstrate that the selectivity determinant of ORC for DNA binding lies in a 19-amino acid insertion helix in the Orc4 subunit, which is present in yeast but absent in human. Removal of this motif from Orc4 transforms the yeast ORC, which selects origins based on base-specific binding at defined locations, into one whose selectivity is dictated by chromatin landscape and afforded with plasticity, as reported for human. Notably, the altered yeast ORC has acquired an affinity for regions near transcriptional start sites (TSSs), which the human ORC also favors., In most model yeast species the Origin Recognition Complex (ORC) binds defined and species-specific base sequences while in humans what determines the binding appears to be more complex. Here the authors reveal that the yeast’s ORC complex binding specificity is dependent on a 19-amino acid insertion helix in the Orc4 subunit which is lost in human.

DNA methylation and covalent histone modifications are precisely and dynamically controlled by various epigenetic modifiers and are critical aspects of transcriptional regulation. Dysregulation of these enzymes results in a wide range of diseases including cancers. In recent years, epigenetic modifiers have become the focus of many cancer treatment studies and clinical trials. Currently, several drugs such as DNA methyltransferase inhibitors and histone deacetylase inhibitors have been approved for clinical use in cancer treatments. However, many more are on the horizon. In this review, we will discuss the roles of DNA methyltransferases, histone acetyltransferases/deacetylases, histone methyltransferases/demethylases, and acetylated histone lysine-binding proteins in oncogenesis and some of the current inhibitors targeting these epigenetic modifiers for therapy.

Using recent survey data, this paper examines access to financing by immigrant business owners. We hypothesize that immigrant and Canadian-born owners finance their businesses in significantly different ways and that immigrant-owned small and medium enterprises (SMEs) have more difficulty accessing financial capital. The results suggest that, after adjusting for firm and owner characteristics, financing sources for growth financing tend to be similar for the two groups. Although immigrant owners—notably those in Canada for more than 20 years—were less likely than Canadian-born owners to seek financing from any source, their applications were as likely to be approved. Both immigrant and Canadian-born owners reported that, among seven potential obstacles to firm growth presented in the survey, “access to financing” was the least important. The study finds only weak evidence to support the hypothesis that access to financial capital is a more serious issue among immigrant-owned SMEs than among SMEs with Canadian-born owners.

This paper provides some of the first empirical evidence on labour market adjustments to exchange rate movements in Canadian manufacturing industries. Controlling for endogeneity using generalized method of moments estimation, it is found that during the 1981–1997 period, exchange movements have a substantial impact on labour input and that this impact has grown over time as the manufacturing industries have become more exposed to trade. In contrast, the exchange rate effect on real wages is estimated to be virtually zero for all manufacturing industries.

Nature 523, 212–216 (2015); doi:10.1038/nature14465 The y-axis label in Fig. 3f of this Letter should read ‘[mCAC/CAC]/[mCAG/CAG]’ rather than ‘[mCAC/CAC]/[mCAC/CAG]’. In addition, in the description of Fig. 4c in the main text, ‘tissue’ and ‘individual’ were swapped; it should read, “Of the ASM events that varied, 4.

Corrigendum: Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET