Publications by authors named "Ephraim Kenigsberg"

20 Publications

  • Page 1 of 1

A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn's disease.

Nature 2021 Mar 31. Epub 2021 Mar 31.

The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Crohn's disease (CD) is a chronic inflammatory intestinal disease, with frequent aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in pathogenicity with increases in intravasating monocytes correlated to anti-TNF treatment non-response. The highest effect risk alleles are loss-of-function NOD2 mutations, which increase risk for stricturing. However, mechanisms underlying NOD2-pathogenicity and salvage pathways in anti-TNF refractory patients remain largely uncharacterized. Here we show that NOD2 loss leads to dysregulated activated fibroblast and macrophage homeostasis by direct ex vivo analyses of patients carrying NOD2 risk alleles. CD14+PBMCs from NOD2 carriers produce collagen-high expressing cells, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. Enrichment of STAT3 regulation and gp130-ligands in activated fibroblasts and macrophages led us to reason that gp130 blockade might rescue the activated program. We correlate post-treatment induction of this pathway in anti-TNF non-responders and demonstrate in vivo amelioration of the activated myeloid-stromal niche, using a specific gp130 inhibitor, bazedoxifene. Our results demonstrate novel biological insights into NOD2-driven fibrosis in CD; gp130 blockade may benefit selected CD patients, potentially complementing anti-TNF therapy.
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http://dx.doi.org/10.1038/s41586-021-03484-5DOI Listing
March 2021

Intestinal host response to SARS-CoV-2 infection and COVID-19 outcomes in patients with gastrointestinal symptoms.

Gastroenterology 2021 Mar 3. Epub 2021 Mar 3.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Background And Aims: Given gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance.

Methods: Human intestinal biopsy tissues were obtained from COVID-19 patients (n=19) and uninfected controls (n=10) for microscopic examination, CyTOF analyses and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in two large, independent cohorts of hospitalized patients in the United States (n=634) and Europe (n=287) using multivariate logistic regressions.

Results: COVID-19 cases and controls in the biopsy cohort were comparable for age, gender, rates of hospitalization and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy, in 14 of 16 patients studied. High dimensional analyses of GI tissues revealed low levels of inflammation, including downregulation of key inflammatory genes including IFNG, CXCL8, CXCL2 and IL1B and reduced frequencies of proinflammatory dendritic cells compared with controls. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of gender, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms.

Conclusion: These data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in COVID-19 patients presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2 associated inflammation needs to be further examined.
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http://dx.doi.org/10.1053/j.gastro.2021.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931673PMC
March 2021

Gastrointestinal involvement attenuates COVID-19 severity and mortality.

medRxiv 2020 Sep 9. Epub 2020 Sep 9.

Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of coronavirus disease 2019 (COVID-19), we investigated the impact of GI infection on disease pathogenesis in three large cohorts of patients in the United States and Europe. Unexpectedly, we observed that GI involvement was associated with a significant reduction in disease severity and mortality, with an accompanying reduction in key inflammatory proteins including IL-6, CXCL8, IL-17A and CCL28 in circulation. In a fourth cohort of COVID-19 patients in which GI biopsies were obtained, we identified severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) within small intestinal enterocytes for the first time in vivo but failed to obtain culturable virus. High dimensional analyses of GI tissues confirmed low levels of cellular inflammation in the GI lamina propria and an active downregulation of key inflammatory genes including IFNG, CXCL8, CXCL2 and IL1B among others. These data draw attention to organ-level heterogeneity in disease pathogenesis and highlight the role of the GI tract in attenuating SARS-CoV-2-associated inflammation with related mortality benefit.
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http://dx.doi.org/10.1101/2020.09.07.20187666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491532PMC
September 2020

A conserved dendritic-cell regulatory program limits antitumour immunity.

Nature 2020 04 25;580(7802):257-262. Epub 2020 Mar 25.

The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Checkpoint blockade therapies have improved cancer treatment, but such immunotherapy regimens fail in a large subset of patients. Conventional type 1 dendritic cells (DC1s) control the response to checkpoint blockade in preclinical models and are associated with better overall survival in patients with cancer, reflecting the specialized ability of these cells to prime the responses of CD8 T cells. Paradoxically, however, DC1s can be found in tumours that resist checkpoint blockade, suggesting that the functions of these cells may be altered in some lesions. Here, using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, we identify a cluster of dendritic cells (DCs) that we name 'mature DCs enriched in immunoregulatory molecules' (mregDCs), owing to their coexpression of immunoregulatory genes (Cd274, Pdcd1lg2 and Cd200) and maturation genes (Cd40, Ccr7 and Il12b). We find that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumour antigens. We further find that upregulation of the programmed death ligand 1 protein-a key checkpoint molecule-in mregDCs is induced by the receptor tyrosine kinase AXL, while upregulation of interleukin (IL)-12 depends strictly on interferon-γ and is controlled negatively by IL-4 signalling. Blocking IL-4 enhances IL-12 production by tumour-antigen-bearing mregDC1s, expands the pool of tumour-infiltrating effector T cells and reduces tumour burden. We have therefore uncovered a regulatory module associated with tumour-antigen uptake that reduces DC1 functionality in human and mouse cancers.
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http://dx.doi.org/10.1038/s41586-020-2134-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787191PMC
April 2020

DNA methylation disruption reshapes the hematopoietic differentiation landscape.

Nat Genet 2020 04 23;52(4):378-387. Epub 2020 Mar 23.

New York Genome Center, New York, NY, USA.

Mutations in genes involved in DNA methylation (DNAme; for example, TET2 and DNMT3A) are frequently observed in hematological malignancies and clonal hematopoiesis. Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid versus myelomonocytic progenitors following Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells. To reconcile genome-wide DNAme changes with specific erythroid versus myelomonocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A-mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motif.
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http://dx.doi.org/10.1038/s41588-020-0595-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216752PMC
April 2020

Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response After Myocardial Infarction.

Circulation 2020 03 29;141(11):916-930. Epub 2020 Jan 29.

Cardiovascular Research Center (Y.H., E.Y., M.M.Ż., E.C., N.S., M.T.K.S., R.K., A.A.K., K.K., A.M., N.H., L.Z., A.F, M.G.K.), Icahn School of Medicine at Mount Sinai, New York.

Background: Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze proapoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase to produce the prosurvival molecule sphingosine-1-phosphate. We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI.

Methods: We performed transcriptomic, sphingolipid, and protein analyses to evaluate sphingolipid metabolism and signaling post-MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA [modRNA]) of AC function post hypoxia or MI.

Results: We found that several genes involved in de novo ceramide synthesis were upregulated and that ceramide (C16, C20, C20:1, and C24) levels had significantly increased 24 hours after MI. AC inhibition after hypoxia or MI resulted in reduced AC activity and increased cell death. By contrast, enhancing AC activity via AC modRNA treatment increased cell survival after hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival, and smaller scar size than control mice 28 days post-MI. We attributed the improvement in heart function post-MI after AC modRNA delivery to decreased ceramide levels, lower cell death rates, and changes in the composition of the immune cell population in the left ventricle manifested by lowered abundance of proinflammatory detrimental neutrophils.

Conclusions: Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post-MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135928PMC
March 2020

Serum Amyloid A Proteins Induce Pathogenic Th17 Cells and Promote Inflammatory Disease.

Cell 2020 01 19;180(1):79-91.e16. Epub 2019 Dec 19.

The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York, NY 10016, USA. Electronic address:

Lymphoid cells that produce interleukin (IL)-17 cytokines protect barrier tissues from pathogenic microbes but are also prominent effectors of inflammation and autoimmune disease. T helper 17 (Th17) cells, defined by RORγt-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4 T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, Th17 cell behaviors vary markedly according to their environment. Here, we show that SAAs additionally direct a pathogenic pro-inflammatory Th17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting Th17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.
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http://dx.doi.org/10.1016/j.cell.2019.11.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039443PMC
January 2020

Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy.

Cell 2019 09 29;178(6):1493-1508.e20. Epub 2019 Aug 29.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Clinical benefits of cytokine blockade in ileal Crohn's disease (iCD) are limited to a subset of patients. Here, we applied single-cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells, and stromal cells, which we named the GIMATS module. Analysis of ligand-receptor interaction pairs identified a distinct network connectivity that likely drives the GIMATS module. Strikingly, the GIMATS module was also present in a subset of patients in four independent iCD cohorts (n = 441), and its presence at diagnosis correlated with failure to achieve durable corticosteroid-free remission upon anti-TNF therapy. These results emphasize the limitations of current diagnostic assays and the potential for single-cell mapping tools to identify novel biomarkers of treatment response and tailored therapeutic opportunities.
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http://dx.doi.org/10.1016/j.cell.2019.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060942PMC
September 2019

MARS-seq2.0: an experimental and analytical pipeline for indexed sorting combined with single-cell RNA sequencing.

Nat Protoc 2019 06 17;14(6):1841-1862. Epub 2019 May 17.

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.

Human tissues comprise trillions of cells that populate a complex space of molecular phenotypes and functions and that vary in abundance by 4-9 orders of magnitude. Relying solely on unbiased sampling to characterize cellular niches becomes infeasible, as the marginal utility of collecting more cells diminishes quickly. Furthermore, in many clinical samples, the relevant cell types are scarce and efficient processing is critical. We developed an integrated pipeline for index sorting and massively parallel single-cell RNA sequencing (MARS-seq2.0) that builds on our previously published MARS-seq approach. MARS-seq2.0 is based on >1 million cells sequenced with this pipeline and allows identification of unique cell types across different tissues and diseases, as well as unique model systems and organisms. Here, we present a detailed step-by-step procedure for applying the method. In the improved procedure, we combine sub-microliter reaction volumes, optimization of enzymatic mixtures and an enhanced analytical pipeline to substantially lower the cost, improve reproducibility and reduce well-to-well contamination. Data analysis combines multiple layers of quality assessment and error detection and correction, graphically presenting key statistics for library complexity, noise distribution and sequencing saturation. Importantly, our combined FACS and single-cell RNA sequencing (scRNA-seq) workflow enables intuitive approaches for depletion or enrichment of cell populations in a data-driven manner that is essential to efficient sampling of complex tissues. The experimental protocol, from cell sorting to a ready-to-sequence library, takes 2-3 d. Sequencing and processing the data through the analytical pipeline take another 1-2 d.
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http://dx.doi.org/10.1038/s41596-019-0164-4DOI Listing
June 2019

Prioritizing Crohn's disease genes by integrating association signals with gene expression implicates monocyte subsets.

Genes Immun 2019 09 29;20(7):577-588. Epub 2019 Jan 29.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA.

Genome-wide association studies have identified ~170 loci associated with Crohn's disease (CD) and defining which genes drive these association signals is a major challenge. The primary aim of this study was to define which CD locus genes are most likely to be disease related. We developed a gene prioritization regression model (GPRM) by integrating complementary mRNA expression datasets, including bulk RNA-Seq from the terminal ileum of 302 newly diagnosed, untreated CD patients and controls, and in stimulated monocytes. Transcriptome-wide association and co-expression network analyses were performed on the ileal RNA-Seq datasets, identifying 40 genome-wide significant genes. Co-expression network analysis identified a single gene module, which was substantially enriched for CD locus genes and most highly expressed in monocytes. By including expression-based and epigenetic information, we refined likely CD genes to 2.5 prioritized genes per locus from an average of 7.8 total genes. We validated our model structure using cross-validation and our prioritization results by protein-association network analyses, which demonstrated significantly higher CD gene interactions for prioritized compared with non-prioritized genes. Although individual datasets cannot convey all of the information relevant to a disease, combining data from multiple relevant expression-based datasets improves prediction of disease genes and helps to further understanding of disease pathogenesis.
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http://dx.doi.org/10.1038/s41435-019-0059-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446136PMC
September 2019

The mutation spectrum in genomic late replication domains shapes mammalian GC content.

Nucleic Acids Res 2016 05 16;44(9):4222-32. Epub 2016 Apr 16.

Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

Genome sequence compositions and epigenetic organizations are correlated extensively across multiple length scales. Replication dynamics, in particular, is highly correlated with GC content. We combine genome-wide time of replication (ToR) data, topological domains maps and detailed functional epigenetic annotations to study the correlations between replication timing and GC content at multiple scales. We find that the decrease in genomic GC content at large scale late replicating regions can be explained by mutation bias favoring A/T nucleotide, without selection or biased gene conversion. Quantification of the free dNTP pool during the cell cycle is consistent with a mechanism involving replication-coupled mutation spectrum that favors AT nucleotides at late S-phase. We suggest that mammalian GC content composition is shaped by independent forces, globally modulating mutation bias and locally selecting on functional element. Deconvoluting these forces and analyzing them on their native scales is important for proper characterization of complex genomic correlations.
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http://dx.doi.org/10.1093/nar/gkw268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872117PMC
May 2016

Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors.

Cell 2015 Dec 25;163(7):1663-77. Epub 2015 Nov 25.

Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

Within the bone marrow, stem cells differentiate and give rise to diverse blood cell types and functions. Currently, hematopoietic progenitors are defined using surface markers combined with functional assays that are not directly linked with in vivo differentiation potential or gene regulatory mechanisms. Here, we comprehensively map myeloid progenitor subpopulations by transcriptional sorting of single cells from the bone marrow. We describe multiple progenitor subgroups, showing unexpected transcriptional priming toward seven differentiation fates but no progenitors with a mixed state. Transcriptional differentiation is correlated with combinations of known and previously undefined transcription factors, suggesting that the process is tightly regulated. Histone maps and knockout assays are consistent with early transcriptional priming, while traditional transplantation experiments suggest that in vivo priming may still allow for plasticity given strong perturbations. These data establish a reference model and general framework for studying hematopoiesis at single-cell resolution.
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http://dx.doi.org/10.1016/j.cell.2015.11.013DOI Listing
December 2015

Massively parallel single-cell RNA-seq for marker-free decomposition of tissues into cell types.

Science 2014 Feb;343(6172):776-9

Department of Immunology, Weizmann Institute, Rehovot 76100, Israel.

In multicellular organisms, biological function emerges when heterogeneous cell types form complex organs. Nevertheless, dissection of tissues into mixtures of cellular subpopulations is currently challenging. We introduce an automated massively parallel single-cell RNA sequencing (RNA-seq) approach for analyzing in vivo transcriptional states in thousands of single cells. Combined with unsupervised classification algorithms, this facilitates ab initio cell-type characterization of splenic tissues. Modeling single-cell transcriptional states in dendritic cells and additional hematopoietic cell types uncovers rich cell-type heterogeneity and gene-modules activity in steady state and after pathogen activation. Cellular diversity is thereby approached through inference of variable and dynamic pathway activity rather than a fixed preprogrammed cell-type hierarchy. These data demonstrate single-cell RNA-seq as an effective tool for comprehensive cellular decomposition of complex tissues.
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http://dx.doi.org/10.1126/science.1247651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412462PMC
February 2014

Drosophila functional elements are embedded in structurally constrained sequences.

PLoS Genet 2013 May 30;9(5):e1003512. Epub 2013 May 30.

Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot, Israel.

Modern functional genomics uncovered numerous functional elements in metazoan genomes. Nevertheless, only a small fraction of the typical non-exonic genome contains elements that code for function directly. On the other hand, a much larger fraction of the genome is associated with significant evolutionary constraints, suggesting that much of the non-exonic genome is weakly functional. Here we show that in flies, local (30-70 bp) conserved sequence elements that are associated with multiple regulatory functions serve as focal points to a pattern of punctuated regional increase in G/C nucleotide frequencies. We show that this pattern, which covers a region tenfold larger than the conserved elements themselves, is an evolutionary consequence of a shift in the balance between gain and loss of G/C nucleotides and that it is correlated with nucleosome occupancy across multiple classes of epigenetic state. Evidence for compensatory evolution and analysis of SNP allele frequencies show that the evolutionary regime underlying this balance shift is likely to be non-neutral. These data suggest that current gaps in our understanding of genome function and evolutionary dynamics are explicable by a model of sparse sequence elements directly encoding for function, embedded into structural sequences that help to define the local and global epigenomic context of such functional elements.
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http://dx.doi.org/10.1371/journal.pgen.1003512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671938PMC
May 2013

Three-dimensional folding and functional organization principles of the Drosophila genome.

Cell 2012 Feb 19;148(3):458-72. Epub 2012 Jan 19.

Institut de Génétique Humaine, UPR 1142, CNRS, 141 rue de la Cardonille, 34396 Montpellier Cedex 5, France.

Chromosomes are the physical realization of genetic information and thus form the basis for its readout and propagation. Here we present a high-resolution chromosomal contact map derived from a modified genome-wide chromosome conformation capture approach applied to Drosophila embryonic nuclei. The data show that the entire genome is linearly partitioned into well-demarcated physical domains that overlap extensively with active and repressive epigenetic marks. Chromosomal contacts are hierarchically organized between domains. Global modeling of contact density and clustering of domains show that inactive domains are condensed and confined to their chromosomal territories, whereas active domains reach out of the territory to form remote intra- and interchromosomal contacts. Moreover, we systematically identify specific long-range intrachromosomal contacts between Polycomb-repressed domains. Together, these observations allow for quantitative prediction of the Drosophila chromosomal contact map, laying the foundation for detailed studies of chromosome structure and function in a genetically tractable system.
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http://dx.doi.org/10.1016/j.cell.2012.01.010DOI Listing
February 2012

Primate CpG islands are maintained by heterogeneous evolutionary regimes involving minimal selection.

Cell 2011 May;145(5):773-86

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel.

Mammalian CpG islands are key epigenomic elements that were first characterized experimentally as genomic fractions with low levels of DNA methylation. Currently, CpG islands are defined based on their genomic sequences alone. Here, we develop evolutionary models to show that several distinct evolutionary processes generate and maintain CpG islands. One central evolutionary regime resulting in enriched CpG content is driven by low levels of DNA methylation and consequentially low rates of CpG deamination. Another major force forming CpG islands is biased gene conversion that stabilizes constitutively methylated CpG islands by balancing rapid deamination with CpG fixation. Importantly, evolutionary analysis and population genetics data suggest that selection for high CpG content is not a significant factor contributing to conservation of CpGs in differentially methylated regions. The heterogeneous, but not selective, origins of CpG islands have direct implications for the understanding of DNA methylation patterns in healthy and diseased cells.
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http://dx.doi.org/10.1016/j.cell.2011.04.024DOI Listing
May 2011

Widespread compensatory evolution conserves DNA-encoded nucleosome organization in yeast.

PLoS Comput Biol 2010 Dec 23;6(12):e1001039. Epub 2010 Dec 23.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

Evolution maintains organismal fitness by preserving genomic information. This is widely assumed to involve conservation of specific genomic loci among species. Many genomic encodings are now recognized to integrate small contributions from multiple genomic positions into quantitative dispersed codes, but the evolutionary dynamics of such codes are still poorly understood. Here we show that in yeast, sequences that quantitatively affect nucleosome occupancy evolve under compensatory dynamics that maintain heterogeneous levels of A+T content through spatially coupled A/T-losing and A/T-gaining substitutions. Evolutionary modeling combined with data on yeast polymorphisms supports the idea that these substitution dynamics are a consequence of weak selection. This shows that compensatory evolution, so far believed to affect specific groups of epistatically linked loci like paired RNA bases, is a widespread phenomenon in the yeast genome, affecting the majority of intergenic sequences in it. The model thus derived suggests that compensation is inevitable when evolution conserves quantitative and dispersed genomic functions.
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http://dx.doi.org/10.1371/journal.pcbi.1001039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3009600PMC
December 2010