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Mineral dust aerosols impact Earth’s energy budget through interactions with radiation, clouds, atmospheric chemistry, the cryosphere and biogeochemistry. In this review, we summarize these interactions and assess the resulting impacts of dust, and of changes in dust, on global climate and climate change. We find that the total effect of these interactions on Earth’s global energy budget—the dust effective radiative effect—is -0.2 ± 0.5 Wm-2 (90% confidence interval). Compared to pre-industrial times, global dust mass loading is 55 ± 30% higher in the modern climate, leading to changes in the Earth’s energy budget. Indeed, this increase in dust has produced a global mean effective radiative forcing of -0.07 ± 0.18 Wm-2. Current climate models and climate assessments do not represent the historical increase in dust and thus omit the resulting radiative forcing, biasing climate change projections and assessments of climate sensitivity. Climate model simulations of future changes in dust diverge widely and are very uncertain. Further work is thus needed to constrain the radiative effects of dust on climate and to improve the representation of dust in climate models.

Adult-onset neurodegenerative diseases are often accompanied by evidence of a chronic inflammation that includes activation of microglial cells and altered levels of brain cytokines. Aspects of this response are likely secondary reactions to neurodegeneration, but for many illnesses the inflammation may itself be an early and even causative disease event. In such cases, the inflammation is referred to as “sterile” as it occurs in the absence of an actual bacterial or viral pathogen. A potent trigger of sterile inflammation in CNS microglia has been shown to be the presence of DNA in the cytoplasm (cytoDNA) induced either by direct DNA damage or by inhibited DNA repair. We have shown that cytoDNA comes from the cell nucleus as a result of insufficient DNA damage repair. Using wild-type andAtm-/-mouse microglia, we extend these observations here by showing that its genomic origins are not random, but rather are heavily biased toward transcriptionally inactive, intergenic regions, in particular repetitive elements and AT-rich sequences. Once released from the genome, in both males and females, we show that cytoDNA is actively exported to the cytoplasm by a CRM1-dependent mechanism. In the cytoplasm, it is degraded either by a cytosolic exonuclease, Trex1, or an autophagy pathway that ends with degradation in the lysosome. Blocking the accumulation of cytoDNA prevents the emergence of the sterile inflammation reaction. These findings offer new insights into the emergence of sterile inflammation and offer novel approaches that may be of use in combatting a wide range of neurodegenerative conditions.SIGNIFICANCE STATEMENTSterile inflammation describes a state where the defenses of the immune system are activated in the absence of a true pathogen. A potent trigger of this unorthodox response is the presence of DNA in the cytoplasm, which immune cells interpret as an invading virus or pathogen. We show that when DNA damage increases, fragments of the cell's own genome are actively exported to the cytoplasm where they are normally degraded. If this degradation is incomplete an immune reaction is triggered. Both age and stress increase DNA damage, and as age-related neurodegenerative diseases are frequently accompanied by a chronic low-level inflammation, strategies that reduce the induction of cytoplasmic DNA or speed its clearance become attractive therapeutic targets.

Replication timing organizes epigenome The temporal order of DNA replication is conserved from yeast to humans, but its biological significance remains unclear. Klein et al. eliminated the protein RIF1, a master regulator of replication timing, in several human cell lines. RIF1 loss during the G1 phase of the cell cycle resulted in a heterogeneous, nearly random replication timing program from the first S phase that persisted even in stable RIF1-null clones. Altered replication timing was followed by replication-dependent redistribution of active and repressive histone modifications and alterations in genome architecture. These results support a model in which replication timing orchestrates the epigenetic state of newly replicated chromatin. Science , this issue p. 371

1AbstractTranscriptional enhancers usually, but not always, regulate genes within the same topologically associating domain (TAD). We hypothesize that this incomplete insulation is due to three-dimensional (3D) structures of TADs: Whereas enhancers and genes buried inside the “core” of a TAD interact mostly with other genomic regions in the same TAD, those on the “surface” can more easily interact with regions outside the TAD. Here we show that a simple measure, the intra-TAD ratio, can quantify the “coreness” of a genomic region with respect to the TAD that it resides in. We further show that TAD surfaces are permissive for high gene expression, and accordingly cell type-specific active cis-regulatory elements (CREs), active histone marks, and transcription factor binding sites are enriched on TAD surfaces, most strongly in chromatin subcompartments typically considered inactive. These findings suggest a “TAD surface CRE” model of gene regulation. In addition, we also find that disease-associated non-coding variants are enriched on TAD surfaces.

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.

To what extent firms are constrained by external credit is usually unobserved in commonly used firm-level data. We use a survey of financing among Canadian small and medium-sized enterprises to measure the likelihood of a firm being constrained by credit. We find that firm size, current debt-to-asset ratio and cash flow are robust indicators of being financially constrained, while long-term debt to asset ratio is not a significant indicator of credit constraints. We then estimate the firm-level total factor productivity, taking into account the measured credit constraints. Omitting credit constraints leads to an upward bias of productivity estimates, by 4 percent. In addition, we find no strong evidence that suggests credit constraints lead to slower productivity growth. Finally, we confirm that both investment and employment growth are negatively affected by the measured credit constraints.

During pregnancy, the maternal-fetal interface plays vital roles in fetal development. Its disruption is frequently found in pregnancy complications. Recent works show increased incidences of adverse pregnancy outcomes in COVID-19 patients; however, the mechanism remains unclear. Here, we analyzed the molecular impacts of SARS-CoV-2 infection on the maternal-fetal interface. Generating bulk and single-nucleus transcriptomic and epigenomic profiles from COVID-19 patients and control samples, we discovered aberrant immune activation and angiogenesis patterns in patients. Surprisingly, retrotransposons were dysregulated in specific cell types. Notably, reduced enhancer activities of LTR8B elements were functionally linked to the downregulation of Pregnancy-Specific Glycoprotein genes in syncytiotrophoblasts. Our findings revealed that SARS-CoV-2 infection induced significant changes to the epigenome and transcriptome at the maternal-fetal interface, which may be associated with pregnancy complications.One-Sentence SummaryPregnant COVID-19 patients show placental epigenetic and transcriptional changes, associated with adverse pregnancy outcomes.

Desert dust is an important aerosol component that produces large uncertainties in assessments of Earth’s radiative budget and global climate change. However, current global climate model (GCM) simulations show that modeled dust poorly captures the observed dust in both spatial and temporal variability, which inhibits accurate assessments of aerosol radiative effects. Furthermore, dust emission is a local-scale process that varies on scales less than 1–10 km and thus current GCMs with typical grid-scale of > 100 km inherently have difficulties capturing dust spatial distribution and its sensitivity to local-scale meteorological variability. To tackle these problems, we develop a new dust emission scheme for GCMs that includes several more physical aeolian processes, and use the Community Earth System Model version 2.1 (CESM2.1) as a case study. First, we account for the dissipation of surface wind momentum by surface roughness elements included plants and rocks, which reduce the wind momentum exerted on the bare soil surface over deserts. The roughness of plants is a function of time-varying leaf area index (LAI), improving the sensitivity of the modeled emissions to climate and land use/land cover (LULC) changes. Second, we account for the effects of soil particle size distribution (PSD) on dust emission threshold by implementing a realistic soil median diameter inferred from a compilation of soil PSD observations. Third, we account for intermittent dust emissions induced by boundary-layer turbulence using a recently proposed saltation parameterization, which further couples dust with boundary-layer dynamics. With more aeolian processes, CESM2 dust emission matches better in spatial variability, seasonality, and dust activation frequency when compared against dust satellite retrievals. Modeled dust aerosol optical depth (DAOD) also shows better agreement in both spatial and temporal correlations with satellite-derived and ground-based AOD. Fourth, in addition to improving the description of aeolian processes, we conduct dust emission simulations across multiple grid resolutions and show that the high-resolution simulations generally produce a better dust spatial distribution. We then generate a map of correction factors to dust emissions for the coarse-gridded simulations to reduce the scale-dependency of dust emission parameterizations, and results indicate further improved agreement with dust observations for coarse-gridded CESM2. Our results suggest that including more physical processes into climate models can lessen bias, improve simulation results, and eliminate the use of empirical source functions. Therefore, our dust emission scheme could improve assessments of dust impacts on the Earth system and future climate changes.

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.

G9a is a lysine methyltransferase that regulates epigenetic modifications, transcription, and genome organization. However, whether these properties are dependent on one another or represent distinct functions of G9a remains unclear. In this study, we observe widespread DNA methylation loss in G9a depleted and catalytic mutant embryonic stem cells. Furthermore, we define how G9a regulates chromatin accessibility, epigenetic modifications, and transcriptional silencing in both catalytic-dependent and -independent manners. Reactivated retrotransposons provide alternative promoters and splice sites leading to the upregulation of neighboring genes and the production of chimeric transcripts. Moreover, while topologically associated domains and compartment A/B definitions are largely unaffected, the loss of G9a leads to altered chromatin states, aberrant CTCF and cohesin binding, and differential chromatin looping, especially at retrotransposons. Taken together, our findings reveal how G9a regulates the epigenome, transcriptome, and higher-order chromatin structures in distinct mechanisms.

DNA is replicated in a defined temporal order termed the replication timing (RT) program. RT is spatially segregated in the nucleus with early/late replication corresponding to Hi-C A/B chromatin compartments, respectively. Early replication is also associated with active histone modifications and transcriptional permissiveness. However, the mechanistic interplay between RT, chromatin state, and genome compartmentalization is largely unknown. Here we report that RT is central to epigenome maintenance and compartmentalization in both human embryonic stem cells (hESCs) and cancer cell line HCT116. Knockout (KO) of the conserved RT control factor RIF1, rather than causing discrete RT switches as previously suspected, lead to dramatically increased cell to cell heterogeneity of RT genome wide, despite RIF1’s enrichment in late replicating chromatin. RIF1 KO hESCs have a nearly random RT program, unlike all prior RIF1 KO cells, including HCT116, which show localized alterations. Regions that retain RT, which are prevalent in HCT116 but rare in hESCs, consist of large H3K9me3 domains revealing two independent mechanisms of RT regulation that are used to different extents in different cell types. RIF1 KO results in a striking genome wide downregulation of H3K27ac peaks and enrichment of H3K9me3 at large domains that remain late replicating, while H3K27me3 and H3K4me3 are re-distributed genome wide in a cell type specific manner. These histone modification changes coincided with global reorganization of genome compartments, transcription changes and a genome wide strengthening of TAD structures. Inducible degradation of RIF1 revealed that disruption of RT is upstream of genome compartmentalization changes. Our findings demonstrate that disruption of RT leads to widespread epigenetic mis-regulation, supporting previously speculative models in which the timing of chromatin assembly at the replication fork plays a key role in maintaining the global epigenetic state, which in turn drives genome architecture.

Michael Chaglasian,1 Murray Fingeret,2 Pinakin Gunvant Davey,3 Wei-Chieh Huang,4 Danny Leung,4 Edmund Ng,5 Charles A Reisman4 1Illinois Eye Institute, Illinois College of Optometry, Chicago, IL, USA; 2Department of Veterans Affairs, New York Harbor Health Care System, Brooklyn, NY, USA; 3School of Optometry, Western University of Health Sciences, Pomona, CA, USA; 4Topcon Healthcare Solutions Research and Development, Oakland, NJ, USA; 5Edmund Ng Consulting, LLC, Seattle, WA, USA Importance: The paper presents the range for measurements taken with a new spectral domain optical coherence tomography (OCT) device to establish a reference database for discrimination purposes. Objective: To report the range of thickness values for the new Topcon Maestro 3D OCT device with 2 scan size settings: the 12×9 mm wide field and 6×6 mm scans. Design: Prospective, multicenter cohort study conducted at 7 clinical sites across the USA. Setting: Primary eyecare clinics within academic, hospital, and private practice locations. Participants: Healthy volunteers; all enrolled participants underwent a complete ophthalmological examination to confirm healthy ocular status prior to being enrolled in the study. Main outcome measure: Average and 1st, 5th, 95th, and 99th percentile ranges for OCT parameters Early Treatment Diabetic Retinopathy Study macula full retinal thickness, ganglion cell + inner plexiform layer thickness (GCL + IPL), ganglion cell complex (GCC) thickness, circumpapillary retinal nerve fiber layer (cpRNFL) thickness. Results: Three hundred and ninety-nine eyes of 399 subjects were included in the analysis. Mean (SD) age was 46.3 (16.3) years (range 18–88 years). Forty-three percent of the subjects were male. Mean (SD) measurements (in μm) for the 12×9 mm wide scan were as follows: foveal thickness=237.079 (20.899), GCL + IPL=71.363 (5.924), GCC=105.949 (8.533), cpRNFL=104.720 (11.829); measurements for the 6×6 mm scans were as follows: foveal thickness=234.000 (20.657), GCL + IPL=71.726 (5.880), GCC=106.698 (9.094), cpRNFL=104.036 (11.341). Conclusion: The overall normal thickness values reported with Topcon 3D OCT-1 Maestro were like those studies with OCT from different manufactures. The reference limits at the 1st, 5th, 95th, and 99th percentile points establish the thresholds for the quantitative comparison of the cpRNFL and the macula in the human retina to a database of known healthy subjects. Keywords: spectral domain optical coherence tomography, normal eyes, 3D OCT-1 Maestro, macular measurements, circumpapillary retinal nerve fiber layer, optic disc

Summary Understanding the diversity of human tissues is fundamental to disease and requires linking genetic information, which is identical in most of an individual’s cells, with epigenetic mechanisms that could play tissue-specific roles. Surveys of DNA methylation in human tissues have established a complex landscape including both tissue-specific and invariant methylation patterns1,2. Here we report high coverage methylomes that catalogue cytosine methylation in all contexts for the major human organ systems, integrated with matched transcriptomes and genomic sequence. By combining these diverse data types with each individuals’ phased genome3, we identified widespread tissue-specific differential CG methylation (mCG), partially methylated domains, allele-specific methylation and transcription, and the unexpected presence of non-CG methylation (mCH) in almost all human tissues. mCH correlated with tissue-specific functions, and using this mark, we made novel predictions of genes that escape X-chromosome inactivation in specific tissues. Overall, DNA methylation in multiple genomic contexts varies substantially among human tissues.

It can be convenient to think of the genome as simply a string of nucleotides, the linear order of which encodes an organism's genetic blueprint. However, the genome does not exist as a linear entity within cells where this blueprint is actually utilized. Inside the nucleus, the genome is organized in three-dimensional (3D) space, and lineage-specific transcriptional programs that direct stem cell fate are implemented in this native 3D context. Here, we review principles of 3D genome organization in mammalian cells. We focus on the emerging relationship between genome organization and lineage-specific transcriptional regulation, which we argue are inextricably linked.

During mammalian development, DNA methylation patterns need to be reset in primordial germ cells (PGCs) and preimplantation embryos. However, many LTR retrotransposons and imprinted genes are impervious to such global epigenetic reprogramming via hitherto undefined mechanisms. Here, we report that a subset of such genomic regions are resistant to widespread erasure of DNA methylation in mouse embryonic stem cells (mESCs) lacking the de novo DNA methyltransferases (Dnmts) Dnmt3a and Dnmt3b. Intriguingly, these loci are enriched for H3K9me3 in mESCs, implicating this mark in DNA methylation homeostasis. Indeed, deletion of the H3K9 methyltransferase SET domain bifurcated 1 (Setdb1) results in reduced H3K9me3 and DNA methylation levels at specific loci, concomitant with increased 5-hydroxymethylation (5hmC) and ten-eleven translocation 1 binding. Taken together, these data reveal that Setdb1 promotes the persistence of DNA methylation in mESCs, likely reflecting one mechanism by which DNA methylation is maintained at LTR retrotransposons and imprinted genes during developmental stages when DNA methylation is reprogrammed.

Item does not contain fulltext The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalog of high-resolution reference epigenomes of major primary human cell types. The studies now presented (see the Cell Press IHEC web portal at http://www.cell.com/consortium/IHEC) highlight the coordinated achievements of IHEC teams to gather and interpret comprehensive epigenomic datasets to gain insights in the epigenetic control of cell states relevant for human health and disease. PAPERCLIP.

The methylcytosine oxidase TET proteins play important roles in DNA demethylation and development. However, it remains elusive how exactly they target substrates and execute oxidation. Interestingly, we found that, in mice, the full-length TET1 isoform (TET1e) is restricted to early embryos, embryonic stem cells (ESCs), and primordial germ cells (PGCs). By contrast, a short isoform (TET1s) is preferentially expressed in somatic cells, which lacks the N terminus including the CXXC domain, a DNA-binding module that often recognizes CpG islands (CGIs) where TET1 predominantly occupies. Unexpectedly, TET1s can still bind CGIs despite the fact that its global chromatin binding is significantly reduced. Interestingly, global chromatin binding, but not targeted binding at CGIs, is correlated with TET1-mediated demethylation. Finally, mice with exclusive expression of Tet1s failed to erase imprints in PGCs and displayed developmental defects in progeny. These data show that isoform switch of TET1 regulates epigenetic memory erasure and mouse development.

The recent financial crisis highlighted the importance of better understanding the interaction between macroeconomic and financial conditions. In this paper, we provide a financial social accounting matrix for the Canadian economy and use it to assess the strength of real-financial linkages by calculating and comparing multipliers with and without endogenous financial flows. It is found that taking into account financial flows increases the impact of a final demand shock on output by 4–11%. Moreover, between 2008 and 2009H1, the investment decisions of financial institutions together with the fact that non-financial institutions were unwilling or unable to increase their financial liabilities led to estimated declines in all GDP multipliers. The impact of a final demand shock on GDP declined 3–5%, while the impact of an increase in the availability of investment funds fell 30% and 55% for financial and non-financial corporations, respectively.† †The views expressed in this paper are those of the authors. ...

Using data on 12 Canadian industries for 1976–2003, this study employs a dynamic panel error correction model to establish the relative importance of potential determinants of Multifactor Productivity (MFP). The model restricts the long run coefficients of these factors to be the same across industries, but allows industry heterogeneity in the short-run coefficients. After controlling for capacity utilization, Information and Communications Technologies (ICT) capital, outsourcing and global trade openness are found to have a statistically significant positive effect on MFP. The long run impact of ICT is small, but its recent contribution to MFP growth is sizeable for some industries, possibly reflecting the delayed benefits of the ICT investment surge in the late 1990s due to adjustment costs. Global trade openness and industry outsourcing generally raises MFP.

DNA methylation and histone H3 lysine 9 trimethylation (H3K9me3) play important roles in silencing of genes and retroelements. However, a comprehensive comparison of genes and repetitive elements repressed by these pathways has not been reported. Here we show that in mouse embryonic stem cells (mESCs), the genes up-regulated following deletion of the H3K9 methyltransferase Setdb1 are distinct from those de-repressed in mESC deficient in the DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b, with the exception of a small number of primarily germline-specific genes. Numerous endogenous retroviruses (ERVs) lose H3K9me3 and are concomitantly de-repressed exclusively in SETDB1 knockout mESCs. Strikingly, ~15% of up-regulated genes are induced in association with de-repression of promoter proximal ERVs, half in the context of “chimaeric” transcripts that initiate within these retroelements and splice to genic exons. Thus, SETDB1 plays a previously unappreciated yet critical role in inhibiting aberrant gene transcription by suppressing the expression of proximal ERVs.

Methylation on lysine 9 of histone H3 (H3K9me) and DNA methylation play important roles in the transcriptional silencing of specific genes and repetitive elements. Both marks are detected on class I and II endogenous retroviruses (ERVs) in murine embryonic stem cells (mESCs). Recently, we reported that the H3K9-specific lysine methyltransferase (KMTase) Eset/Setdb1/KMT1E is required for H3K9me3 and the maintenance of silencing of ERVs in mESCs. In contrast, G9a/Ehmt2/KMT1C is dispensable, despite the fact that this KMTase is required for H3K9 dimethylation (H3K9me2) and efficient DNA methylation of these retroelements. Transcription of the exogenous retrovirus (XRV) Moloney murine leukemia virus is rapidly extinguished after integration in mESCs, concomitant with de novo DNA methylation. However, the role that H3K9 KMTases play in this process has not been addressed. Here, we demonstrate that G9a, but not Suv39h1 or Suv39h2, is required for silencing of newly integrated Moloney murine leukemia virus–based vectors in mESCs. The silencing defect in G9a −/− cells is accompanied by a reduction of H3K9me2 at the proviral LTR, indicating that XRVs are direct targets of G9a. Furthermore, de novo DNA methylation of newly integrated proviruses is impaired in the G9a −/− line, phenocopying proviral DNA methylation and silencing defects observed in Dnmt3a-deficient mESCs. Once established, however, maintenance of silencing of XRVs, like ERVs, is dependent exclusively on the KMTase Eset. Taken together, these observations reveal that in mESCs, the H3K9 KMTase G9a is required for the establishment, but not for the maintenance, of silencing of newly integrated proviruses.

Using industry-level data for Canadian manufacturing industries from 1981 to 1997, we find empirical evidence of a negative relationship between the capital–labour ratio and the user cost of capital relative to the price of labour. A 10% increase in the user cost of the Machinery and Equipment (M&E) relative to the price of labour results in a 3.3% decrease in the M&E–labour ratio in the long run. Assuming complete exchange rate pass-through into imported M&E prices, the maximum effect of a permanent 10% depreciation in the exchange rate is a 1.7% decline in the M&E–labour ratio. This result implies that the cumulative growth of the M&E–labour ratio during the 1991 to 1997 period would have been 2.3 percentage points higher had the dollar not depreciated. This may appear to be significant, but considering both M&E as a share of total capital and the capital share of nominal output are both approximately one-third, in terms of a simple growth accounting framework, the effect on labour productivity is small.

Histone H3K9 methylation is required for DNA methylation and silencing of repetitive elements in plants and filamentous fungi. In mammalian cells however, deletion of the H3K9 histone methyltransferases (HMTases) Suv39h1 and Suv39h2 does not affect DNA methylation of the endogenous retrovirus murine leukaemia virus, indicating that H3K9 methylation is dispensable for DNA methylation of retrotransposons, or that a different HMTase is involved. We demonstrate that embryonic stem (ES) cells lacking the H3K9 HMTase G9a show a significant reduction in DNA methylation of retrotransposons, major satellite repeats and densely methylated CpG-rich promoters. Surprisingly, demethylated retrotransposons remain transcriptionally silent in G9a(-/-) cells, and show only a modest decrease in H3K9me2 and no decrease in H3K9me3 or HP1alpha binding, indicating that H3K9 methylation per se is not the relevant trigger for DNA methylation. Indeed, introduction of catalytically inactive G9a transgenes partially 'rescues' the DNA methylation defect observed in G9a(-/-) cells. Taken together, these observations reveal that H3K9me3 and HP1alpha recruitment to retrotransposons occurs independent of DNA methylation in ES cells and that G9a promotes DNA methylation independent of its HMTase activity.

The research findings highlighted in this article suggest that firm-size differences play a significant role in explaining the productivity gap between Canada and the United States. The authors review factors that lead to a positive relationship between productivity and size and then look at Canadian evidence of this relationship at the firm level. They quantify the extent to which the change in Canadian productivity as well as the Canada-U.S. productivity differences can be accounted for by the change in the importance of large firms and identify several factors that play a role in determining average firm size and aggregate productivity.

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.

This paper examines the gender differences in the choice to become self-employed. Of particular interest is the relationship between the male/female earnings gap in wage and self-employment, and the male/female differences in the average predicted probability of self-employment. It has been argued that earnings inequality in wage-employment lead women to choose self-employment. However, it may be the case that inequality in the form of consumer discrimination causes an earnings gap between males and females in self-employment. If inequality is higher in self-employment than in wage-employment, then there would be females in wage-employment who would be in self-employment in the absence of inequality in both sectors.

The Hong Kong system is unique in the sense that its enforcement regime comprises of two separate bodies, namely the HKCC and the Tribunal. Danny Leung & Stephanie Tsui (Hogan Lovells)

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease., National Human Genome Research Institute (U.S.) (RC1HG005334), National Human Genome Research Institute (U.S.) (R01HG004037), National Human Genome Research Institute (U.S.) (R01HG004037-S1), National Human Genome Research Institute (U.S.) (RO1NS078839), National Science Foundation (U.S.) (CAREER Award 1254200)

As part of the Epigenome Roadmap project, this study uses a chromosome-spanning haplotype reconstruction strategy to construct haplotype-resolved epigenomic maps for a diverse set of human tissues; the maps reveal extensive allelic biases in chromatin state and transcription, which vary across individuals due to genetic backgrounds. As part of the Epigenome Roadmap project, Bing Ren and colleagues use a chromosome-spanning haplotype reconstruction strategy to construct haplotype-resolved epigenomic maps for a diverse set of human tissues. The maps reveal extensive allelic biases in chromatin state and transcription, which vary across tissues and between individuals. They authors investigate cis-regulatory relationships between genes and their control sequences and tissue-restricted activities of repetitive elements. Allelic differences between the two homologous chromosomes can affect the propensity of inheritance in humans; however, the extent of such differences in the human genome has yet to be fully explored. Here we delineate allelic chromatin modifications and transcriptomes among a broad set of human tissues, enabled by a chromosome-spanning haplotype reconstruction strategy1. The resulting large collection of haplotype-resolved epigenomic maps reveals extensive allelic biases in both chromatin state and transcription, which show considerable variation across tissues and between individuals, and allow us to investigate cis-regulatory relationships between genes and their control sequences. Analyses of histone modification maps also uncover intriguing characteristics of cis-regulatory elements and tissue-restricted activities of repetitive elements. The rich data sets described here will enhance our understanding of the mechanisms by which cis-regulatory elements control gene expression programs.

SummaryEpigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To investigate epigenetic regulation of embryonic development, we differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast-like cells, and mesenchymal stem cells and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage. We found that promoters that are active in early developmental stages tend to be CG rich and mainly engage H3K27me3 upon silencing in nonexpressing lineages. By contrast, promoters for genes expressed preferentially at later stages are often CG poor and primarily employ DNA methylation upon repression. Interestingly, the early developmental regulatory genes are often located in large genomic domains that are generally devoid of DNA methylation in most lineages, which we termed DNA methylation valleys (DMVs). Our results suggest that distinct epigenetic mechanisms regulate early and late stages of ES cell differentiation.

Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Using human, Drosophila and mouse models, we show that the proteins encoded by SMARCAL1 orthologs localize to transcriptionally active chromatin and modulate gene expression. We also show that, as found in SIOD patients, deficiency of the SMARCAL1 orthologs alone is insufficient to cause disease in fruit flies and mice, although such deficiency causes modest diffuse alterations in gene expression. Rather, disease manifests when SMARCAL1 deficiency interacts with genetic and environmental factors that further alter gene expression. We conclude that the SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in gene expression contribute to the penetrance of SIOD.

This paper asks how and why the transition rates for males between non-employment, paid employment, own-account self-employment, and self-employment with paid help changed in Canada between the 1990s and the 2000s. It is found that the self-employed were much less likely to move back into paid employment in the 2000s than they were in the 1990s. Estimates from a dynamic mixed multinomial logit model suggest that increased state dependence, not demographic change or changes in the industrial and occupational structure, accounts for the increased stability. Since the productivity of entrants has been found in the literature to be less than that of incumbents, the fact that there were more newly self-employed in the 1990s and that their businesses did not survive long is likely related to the poorer productivity performance of the self-employment sector in the 1990s compared to that of the self-employment sector in the 2000s.

Retrotransposons, such as endogenous retroviruses (ERVs), have colonized the genomes of all metazoans. As retrotransposition can be deleterious, numerous pathways have evolved to repress the expression of these parasitic elements. For example, methylation of the fifth carbon of the cytosine base in DNA (5-methylcytosine, 5mC) is required for transcriptional silencing of ERVs in differentiated cells. However, this epigenetic mark is generally dispensable for ERV silencing during early stages of mouse embryogenesis and in mouse embryonic stem cells (mESCs). In this Opinion, we evaluate recent findings on the exceptional role of covalent modifications of histones in ERV silencing in these cell types. In addition, we discuss the potential role of TET proteins, which catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), in perturbing transcriptional silencing, and propose that histone modification-based pathways may be used to silence ERVs during those developmental stages when DNA methylation-mediated silencing is compromised.