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Article ; Online: Comprehensive annotations of human herpesvirus 6A and 6B genomes reveal novel and conserved genomic features

Yaara Finkel / Dominik Schmiedel / Julie Tai-Schmiedel / Aharon Nachshon / Roni Winkler / Martina Dobesova / Michal Schwartz / Ofer Mandelboim / Noam Stern-Ginossar

eLife, Vol

2020 Volume 9

Abstract: Human herpesvirus-6 (HHV-6) A and B are ubiquitous betaherpesviruses, infecting the majority of the human population. They encompass large genomes and our understanding of their protein coding potential is far from complete. Here, we employ ribosome- ... ...

Abstract	Human herpesvirus-6 (HHV-6) A and B are ubiquitous betaherpesviruses, infecting the majority of the human population. They encompass large genomes and our understanding of their protein coding potential is far from complete. Here, we employ ribosome-profiling and systematic transcript-analysis to experimentally define HHV-6 translation products. We identify hundreds of new open reading frames (ORFs), including upstream ORFs (uORFs) and internal ORFs (iORFs), generating a complete unbiased atlas of HHV-6 proteome. By integrating systematic data from the prototypic betaherpesvirus, human cytomegalovirus, we uncover numerous uORFs and iORFs conserved across betaherpesviruses and we show uORFs are enriched in late viral genes. We identified three highly abundant HHV-6 encoded long non-coding RNAs, one of which generates a non-polyadenylated stable intron appearing to be a conserved feature of betaherpesviruses. Overall, our work reveals the complexity of HHV-6 genomes and highlights novel features conserved between betaherpesviruses, providing a rich resource for future functional studies.
Keywords	human herpesvirus 6 ; cytomegalovirus ; ribosome profiling ; genome annotations ; lncRNA ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Regulatory chromatin landscape in Arabidopsis thaliana roots uncovered by coupling INTACT and ATAC-seq

Miriam Tannenbaum / Avital Sarusi-Portuguez / Ronen Krispil / Michal Schwartz / Olga Loza / Jennifer I. C. Benichou / Assaf Mosquna / Ofir Hakim

Plant Methods, Vol 14, Iss 1, Pp 1-

2018 Volume 12

Abstract: Abstract Background There is a growing interest in the role of chromatin in acquiring and maintaining cell identity. Despite the ever-growing availability of genome-wide gene expression data, understanding how transcription programs are established and ... ...

Abstract	Abstract Background There is a growing interest in the role of chromatin in acquiring and maintaining cell identity. Despite the ever-growing availability of genome-wide gene expression data, understanding how transcription programs are established and regulated to define cell identity remains a puzzle. An important mechanism of gene regulation is the binding of transcription factors (TFs) to specific DNA sequence motifs across the genome. However, these sequences are hindered by the packaging of DNA to chromatin. Thus, the accessibility of these loci for TF binding is highly regulated and determines where and when TFs bind. We present a workflow for measuring chromatin accessibility in Arabidopsis thaliana and define organ-specific regulatory sites and binding motifs of TFs at these sites. Results We coupled the recently described isolation of nuclei tagged in specific cell types (INTACT) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) as a genome-wide strategy to uncover accessible regulatory sites in Arabidopsis based on their accessibility to nuclease digestion. By applying this pipeline in Arabidopsis roots, we revealed 41,419 accessible sites, of which approximately half are found in gene promoters and contain the H3K4me3 active histone mark. The root-unique accessible sites from this group are enriched for root processes. Interestingly, most of the root-unique accessible sites are found in nongenic regions but are correlated with root-specific expression of distant genes. Importantly, these gene-distant sites are enriched for binding motifs of TFs important for root development as well as motifs for TFs that may play a role as novel transcriptional regulators in roots, suggesting that these accessible loci are functional novel gene-distant regulatory elements. Conclusions By coupling INTACT with ATAC-seq methods, we present a feasible pipeline to profile accessible chromatin in plants. We also introduce a rapid measure of the experiment quality. We find that ...
Keywords	Chromatin accessibility ; Chromatin structure ; Regulatory element ; Transcription ; Transcription factor ; Arabidopsis thaliana ; Plant culture ; SB1-1110 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2018-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genomic retargeting of p53 and CTCF is associated with transcriptional changes during oncogenic HRas-induced transformation

Michal Schwartz / Avital Sarusi Portugez / Bracha Zukerman Attia / Miriam Tannenbaum / Leslie Cohen / Olga Loza / Emily Chase / Yousef Turman / Tommy Kaplan / Zaidoun Salah / Ofir Hakim

Communications Biology, Vol 3, Iss 1, Pp 1-

2020 Volume 13

Abstract: By integrating transcriptome, regulatory element and chromosome topology profiles, Schwartz et al identify redistribution of p53 and CTCF genomic binding to be associated with transcriptional and phenotypical changes during Ras-induced transformation of ... ...

Abstract	By integrating transcriptome, regulatory element and chromosome topology profiles, Schwartz et al identify redistribution of p53 and CTCF genomic binding to be associated with transcriptional and phenotypical changes during Ras-induced transformation of mammary epithelial cells.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Human cytomegalovirus long noncoding RNA4.9 regulates viral DNA replication.

Julie Tai-Schmiedel / Sharon Karniely / Betty Lau / Adi Ezra / Erez Eliyahu / Aharon Nachshon / Karen Kerr / Nicolás Suárez / Michal Schwartz / Andrew J Davison / Noam Stern-Ginossar

PLoS Pathogens, Vol 16, Iss 4, p e

2020 Volume 1008390

Abstract: Viruses are known for their extremely compact genomes composed almost entirely of protein-coding genes. Nonetheless, four long noncoding RNAs (lncRNAs) are encoded by human cytomegalovirus (HCMV). Although these RNAs accumulate to high levels during ... ...

Abstract	Viruses are known for their extremely compact genomes composed almost entirely of protein-coding genes. Nonetheless, four long noncoding RNAs (lncRNAs) are encoded by human cytomegalovirus (HCMV). Although these RNAs accumulate to high levels during lytic infection, their functions remain largely unknown. Here, we show that HCMV-encoded lncRNA4.9 localizes to the viral nuclear replication compartment, and that its depletion restricts viral DNA replication and viral growth. RNA4.9 is transcribed from the HCMV origin of replication (oriLyt) and forms an RNA-DNA hybrid (R-loop) through its G+C-rich 5' end, which may be important for the initiation of viral DNA replication. Furthermore, targeting the RNA4.9 promoter with CRISPR-Cas9 or genetic relocalization of oriLyt leads to reduced levels of the viral single-stranded DNA-binding protein (ssDBP), suggesting that the levels of ssDBP are coupled to the oriLyt activity. We further identified a similar, oriLyt-embedded, G+C-rich lncRNA in murine cytomegalovirus (MCMV). These results indicate that HCMV RNA4.9 plays an important role in regulating viral DNA replication, that the levels of ssDBP are coupled to the oriLyt activity, and that these regulatory features may be conserved among betaherpesviruses.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Single cell analysis reveals human cytomegalovirus drives latently infected cells towards an anergic-like monocyte state

Miri Shnayder / Aharon Nachshon / Batsheva Rozman / Biana Bernshtein / Michael Lavi / Noam Fein / Emma Poole / Selmir Avdic / Emily Blyth / David Gottlieb / Allison Abendroth / Barry Slobedman / John Sinclair / Noam Stern-Ginossar / Michal Schwartz

eLife, Vol

2020 Volume 9

Abstract: Human cytomegalovirus (HCMV) causes a lifelong infection through establishment of latency. Although reactivation from latency can cause life-threatening disease, our molecular understanding of HCMV latency is incomplete. Here we use single cell RNA-seq ... ...

Abstract	Human cytomegalovirus (HCMV) causes a lifelong infection through establishment of latency. Although reactivation from latency can cause life-threatening disease, our molecular understanding of HCMV latency is incomplete. Here we use single cell RNA-seq analysis to characterize latency in monocytes and hematopoietic stem and progenitor cells (HSPCs). In monocytes, we identify host cell surface markers that enable enrichment of latent cells harboring higher viral transcript levels, which can reactivate more efficiently, and are characterized by reduced intrinsic immune response that is important for viral gene expression. Significantly, in latent HSPCs, viral transcripts could be detected only in monocyte progenitors and were also associated with reduced immune-response. Overall, our work indicates that regardless of the developmental stage in which HCMV infects, HCMV drives hematopoietic cells towards a weaker immune-responsive monocyte state and that this anergic-like state is crucial for the virus ability to express its transcripts and to eventually reactivate.
Keywords	cytomegalovirus ; herpesvirus ; latency ; single-cell RNA-seq ; reactivation ; hematopoietic stem and progenitor cells ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Parsing the role of NSP1 in SARS-CoV-2 infection

Tal Fisher / Avi Gluck / Krishna Narayanan / Makoto Kuroda / Aharon Nachshon / Jason C. Hsu / Peter J. Halfmann / Yfat Yahalom-Ronen / Hadas Tamir / Yaara Finkel / Michal Schwartz / Shay Weiss / Chien-Te K. Tseng / Tomer Israely / Nir Paran / Yoshihiro Kawaoka / Shinji Makino / Noam Stern-Ginossar

Cell Reports, Vol 39, Iss 11, Pp 110954- (2022)

2022

Abstract: Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to shutoff of protein synthesis, and nsp1, a central shutoff factor in coronaviruses, inhibits cellular mRNA translation. However, the diverse molecular mechanisms employed by ... ...

Abstract	Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to shutoff of protein synthesis, and nsp1, a central shutoff factor in coronaviruses, inhibits cellular mRNA translation. However, the diverse molecular mechanisms employed by nsp1 as well as its functional importance are unresolved. By overexpressing various nsp1 mutants and generating a SARS-CoV-2 mutant, we show that nsp1, through inhibition of translation and induction of mRNA degradation, targets translated cellular mRNA and is the main driver of host shutoff during infection. The propagation of nsp1 mutant virus is inhibited exclusively in cells with intact interferon (IFN) pathway as well as in vivo, in hamsters, and this attenuation is associated with stronger induction of type I IFN response. Therefore, although nsp1’s shutoff activity is broad, it plays an essential role, specifically in counteracting the IFN response. Overall, our results reveal the multifaceted approach nsp1 uses to shut off cellular protein synthesis and uncover nsp1’s explicit role in blocking the IFN response.
Keywords	SARS-CoV-2 ; Nsp1 ; RNA ; Interferon ; Host shutoff ; Translation regulation ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model

Neta Rosenzweig / Raz Dvir-Szternfeld / Afroditi Tsitsou-Kampeli / Hadas Keren-Shaul / Hila Ben-Yehuda / Pierre Weill-Raynal / Liora Cahalon / Alex Kertser / Kuti Baruch / Ido Amit / Assaf Weiner / Michal Schwartz

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 15

Abstract: Blocking the PD-1 pathway was shown to be effective in amyloid beta mouse models, yet little is known about its therapeutic potential in models of tauopathy. The authors show here that blocking PD-L1, a PD-1 ligand, is similarly effective, and that both ... ...

Abstract	Blocking the PD-1 pathway was shown to be effective in amyloid beta mouse models, yet little is known about its therapeutic potential in models of tauopathy. The authors show here that blocking PD-L1, a PD-1 ligand, is similarly effective, and that both treatments reversed cognitive deficiencies, and modified disease pathology not only in an animal model of AD, but also in the DM-hTAU mouse tauopathy model, through a mechanism that involves monocyte-derived macrophages.
Keywords	Science ; Q
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The glial scar-monocyte interplay

Ravid Shechter / Catarina Raposo / Anat London / Irit Sagi / Michal Schwartz

PLoS ONE, Vol 6, Iss 12, p e

a pivotal resolution phase in spinal cord repair.

2011 Volume 27969

Abstract: The inflammatory response in the injured spinal cord, an immune privileged site, has been mainly associated with the poor prognosis. However, recent data demonstrated that, in fact, some leukocytes, namely monocytes, are pivotal for repair due to their ... ...

Abstract	The inflammatory response in the injured spinal cord, an immune privileged site, has been mainly associated with the poor prognosis. However, recent data demonstrated that, in fact, some leukocytes, namely monocytes, are pivotal for repair due to their alternative anti-inflammatory phenotype. Given the pro-inflammatory milieu within the traumatized spinal cord, known to skew monocytes towards a classical phenotype, a pertinent question is how parenchymal-invading monocytes acquire resolving properties essential for healing, under such unfavorable conditions. In light of the spatial association between resolving (interleukin (IL)-10 producing) monocytes and the glial scar matrix chondroitin sulfate proteoglycan (CSPG), in this study we examined the mutual relationship between these two components. By inhibiting the de novo production of CSPG following spinal cord injury, we demonstrated that this extracellular matrix, mainly known for its ability to inhibit axonal growth, serves as a critical template skewing the entering monocytes towards the resolving phenotype. In vitro cell culture studies demonstrated that this matrix alone is sufficient to induce such monocyte polarization. Reciprocal conditional ablation of the monocyte-derived macrophages concentrated at the lesion margins, using diphtheria toxin, revealed that these cells have scar matrix-resolving properties. Replenishment of monocytic cell populations to the ablated mice demonstrated that this extracellular remodeling ability of the infiltrating monocytes requires their expression of the matrix-degrading enzyme, matrix metalloproteinase 13 (MMP-13), a property that was found here to be crucial for functional recovery. Altogether, this study demonstrates that the glial scar-matrix, a known obstacle to regeneration, is a critical component skewing the encountering monocytes towards a resolving phenotype. In an apparent feedback loop, monocytes were found to regulate scar resolution. This cross-regulation between the glial scar and monocytes primes the resolution of this interim phase of spinal cord repair, thereby providing a fundamental platform for the dynamic healing response.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparative analysis of T4 DNA ligases and DNA polymerases used in chromosome conformation capture assays

Michal Schwartz / Avital Sarusi / Rachel T. Deitch / Moran Tal / Dana Raz / Myong-Hee Sung / Tommy Kaplan / Ofir Hakim

BioTechniques, Vol 58, Iss 4, Pp 195-

2015 Volume 199

Abstract: Three-dimensional (3-D) genome organization in the nuclear space affects various genomic functions. Circular chromosome conformation capture (4C-seq) is a powerful technique that allows researchers to measure long-range chromosomal interactions with a ... ...

Abstract	Three-dimensional (3-D) genome organization in the nuclear space affects various genomic functions. Circular chromosome conformation capture (4C-seq) is a powerful technique that allows researchers to measure long-range chromosomal interactions with a locus of interest across the entire genome. This method relies on enzymatic cleavage of cross-linked chromatin and consecutive ligation to create ligation junctions between physically adjacent loci, followed by PCR amplification of locus-specific associating loci. The enzymes used must meet 4C standards because variations in their efficiency and performance may affect the quality of the obtained data. Here we systematically compare the efficiency and reliability of different T4 DNA ligases and PCR DNA polymerases, assessing the most critical and technically challenging steps in 4C. The results of this analysis enable the use of cost-effective enzymes with superior specificity and efficiency for 4C and save time in screening for appropriate primers. This information provides users with flexibility in their experimental design and guidelines for adapting and testing any enzyme of choice for obtaining standardized results.
Keywords	chromosome conformation capture ; 3C ; 4C ; nuclear architecture ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2015-04-01T00:00:00Z
Publisher	Future Science Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Hierarchical role for transcription factors and chromatin structure in genome organization along adipogenesis

Sarusi Portuguez, Avital / Michal Schwartz / MyongâHee Sung / Ofir Hakim / Rasmus Siersbaek / Ronni Nielsen / Susanne Mandrup / Tommy Kaplan

FEBS journal. 2017 Oct., v. 284, no. 19

2017

Abstract: The three dimensional folding of mammalian genomes is cell type specific and difficult to alter suggesting that it is an important component of gene regulation. However, given the multitude of chromatinâassociating factors, the mechanisms driving the ... ...

Abstract	The three dimensional folding of mammalian genomes is cell type specific and difficult to alter suggesting that it is an important component of gene regulation. However, given the multitude of chromatinâassociating factors, the mechanisms driving the colocalization of active chromosomal domains and the role of this organization in regulating the transcription program in adipocytes are not clear. Analysis of genomeâwide chromosomal associations revealed cell typeâspecific spatial clustering of adipogenic genes in 3T3âL1 cells. Time course analysis demonstrated that the adipogenic âhubâ, sampled by PPARÎ³ and Lpin1, undergoes orchestrated reorganization during adipogenesis. Coupling the dynamics of genome architecture with multiple chromatin datasets indicated that among all the transcription factors (TFs) tested, RXR is central to genome reorganization at the beginning of adipogenesis. Interestingly, at the end of differentiation, the adipogenic hub was shifted to an H3K27me3ârepressive environment in conjunction with attenuation of gene transcription. We propose a stageâspecific hierarchy for the activity of TFs contributing to the establishment of an adipogenic genome architecture that brings together the adipogenic genetic program. In addition, the repositioning of this network in a H3K27me3ârich environment at the end of differentiation may contribute to the stabilization of gene transcription levels and reduce the developmental plasticity of these specialized cells. DATABASE: All sequence data reported in this paper have been deposited at GEO (http://www.ncbi.nlm.nih.gov/geo/) (GSE92475)
Keywords	adipocytes ; adipogenesis ; chromatin ; data collection ; genes ; mammals ; plasticity ; transcription (genetics) ; transcription factors
Language	English
Dates of publication	2017-10
Size	p. 3230-3244.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.14183
Database	NAL-Catalogue (AGRICOLA)

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