Imperial College London

ProfessorBorisLenhard

Faculty of MedicineInstitute of Clinical Sciences

Professor of Computational Biology
 
 
 
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Contact

 

+44 (0)20 7594 0911b.lenhard Website

 
 
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Assistant

 

Mr Alastair Douglas Ivor Williams +44 (0)20 3313 4318

 
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Location

 

6.12CLMS BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

194 results found

Rauluseviciute I, Riudavets-Puig R, Blanc-Mathieu R, Castro-Mondragon JA, Ferenc K, Kumar V, Lemma RB, Lucas J, Chèneby J, Baranasic D, Khan A, Fornes O, Gundersen S, Johansen M, Hovig E, Lenhard B, Sandelin A, Wasserman WW, Parcy F, Mathelier Aet al., 2024, JASPAR 2024: 20th anniversary of the open-access database of transcription factor binding profiles., Nucleic Acids Res, Vol: 52, Pages: D174-D182

JASPAR (https://jaspar.elixir.no/) is a widely-used open-access database presenting manually curated high-quality and non-redundant DNA-binding profiles for transcription factors (TFs) across taxa. In this 10th release and 20th-anniversary update, the CORE collection has expanded with 329 new profiles. We updated three existing profiles and provided orthogonal support for 72 profiles from the previous release's UNVALIDATED collection. Altogether, the JASPAR 2024 update provides a 20% increase in CORE profiles from the previous release. A trimming algorithm enhanced profiles by removing low information content flanking base pairs, which were likely uninformative (within the capacity of the PFM models) for TFBS predictions and modelling TF-DNA interactions. This release includes enhanced metadata, featuring a refined classification for plant TFs' structural DNA-binding domains. The new JASPAR collections prompt updates to the genomic tracks of predicted TF binding sites (TFBSs) in 8 organisms, with human and mouse tracks available as native tracks in the UCSC Genome browser. All data are available through the JASPAR web interface and programmatically through its API and the updated Bioconductor and pyJASPAR packages. Finally, a new TFBS extraction tool enables users to retrieve predicted JASPAR TFBSs intersecting their genomic regions of interest.

Journal article

Nikumbh S, Lenhard B, 2023, Identifying promoter sequence architectures via a chunking-based algorithm using non-negative matrix factorisation., PLoS Comput Biol, Vol: 19

Core promoters are stretches of DNA at the beginning of genes that contain information that facilitates the binding of transcription initiation complexes. Different functional subsets of genes have core promoters with distinct architectures and characteristic motifs. Some of these motifs inform the selection of transcription start sites (TSS). By discovering motifs with fixed distances from known TSS positions, we could in principle classify promoters into different functional groups. Due to the variability and overlap of architectures, promoter classification is a difficult task that requires new approaches. In this study, we present a new method based on non-negative matrix factorisation (NMF) and the associated software called seqArchR that clusters promoter sequences based on their motifs at near-fixed distances from a reference point, such as TSS. When combined with experimental data from CAGE, seqArchR can efficiently identify TSS-directing motifs, including known ones like TATA, DPE, and nucleosome positioning signal, as well as novel lineage-specific motifs and the function of genes associated with them. By using seqArchR on developmental time courses, we reveal how relative use of promoter architectures changes over time with stage-specific expression. seqArchR is a powerful tool for initial genome-wide classification and functional characterisation of promoters. Its use cases are more general: it can also be used to discover any motifs at near-fixed distances from a reference point, even if they are present in only a small subset of sequences.

Journal article

Al-Jibury E, King JWD, Guo Y, Lenhard B, Fisher AG, Merkenschlager M, Rueckert Det al., 2023, A deep learning method for replicate-based analysis of chromosome conformation contacts using Siamese neural networks, Nature Communications, Vol: 14, ISSN: 2041-1723

The organisation of the genome in nuclear space is an important frontier of biology. Chromosome conformation capture methods such as Hi-C and Micro-C produce genome-wide chromatin contact maps that provide rich data containing quantitative and qualitative information about genome architecture. Most conventional approaches to genome-wide chromosome conformation capture data are limited to the analysis of pre-defined features, and may therefore miss important biological information. One constraint is that biologically important features can be masked by high levels of technical noise in the data. Here we introduce a replicate-based method for deep learning from chromatin conformation contact maps. Using a Siamese network configuration our approach learns to distinguish technical noise from biological variation and outperforms image similarity metrics across a range of biological systems. The features extracted from Hi-C maps after perturbation of cohesin and CTCF reflect the distinct biological functions of cohesin and CTCF in the formation of domains and boundaries, respectively. The learnt distance metrics are biologically meaningful, as they mirror the density of cohesin and CTCF binding. These properties make our method a powerful tool for the exploration of chromosome conformation capture data, such as Hi-C capture Hi-C, and Micro-C.

Journal article

McAllan L, Baranasic D, Villicaña S, Brown S, Zhang W, Lehne B, Adamo M, Jenkinson A, Elkalaawy M, Mohammadi B, Hashemi M, Fernandes N, Lambie N, Williams R, Christiansen C, Yang Y, Zudina L, Lagou V, Tan S, Castillo-Fernandez J, King JWD, Soong R, Elliott P, Scott J, Prokopenko I, Cebola I, Loh M, Lenhard B, Batterham RL, Bell JT, Chambers JC, Kooner JS, Scott WRet al., 2023, Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes, Nature Communications, Vol: 14, Pages: 1-20, ISSN: 2041-1723

DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.

Journal article

Paterson HAB, Yu S, Artigas N, Prado MA, Haberman N, Wang Y-F, Jobbins AM, Pahita E, Mokochinski J, Hall Z, Guerin M, Paulo JA, Ng SS, Villarroya F, Rashid ST, Le Goff W, Lenhard B, Cebola I, Finley D, Gygi SP, Sibley CR, Vernia Set al., 2022, Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice, Nature Metabolism, Vol: 4, Pages: 1812-1829, ISSN: 2522-5812

RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein 2 (RBFOX2) in maintaining cholesterol homeostasis in a lipogenic environment in the liver. Using enhanced individual-nucleotide-resolution ultra-violet cross-linking and immunoprecipitation, we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesity-induced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases.

Journal article

Guo Y, Al-Jibury E, Garcia-Millan R, Ntagiantas K, King JWD, Nash AJ, Galjart N, Lenhard B, Rueckert D, Fisher AG, Pruessner G, Merkenschlager Met al., 2022, Chromatin jets define the properties of cohesin-driven in vivo loop extrusion, Molecular Cell, Vol: 82, Pages: 3769-3780.e5, ISSN: 1097-2765

Complex genomes show intricate organization in three-dimensional (3D) nuclear space. Current models posit that cohesin extrudes loops to form self-interacting domains delimited by the DNA binding protein CTCF. Here, we describe and quantitatively characterize cohesin-propelled, jet-like chromatin contacts as landmarks of loop extrusion in quiescent mammalian lymphocytes. Experimental observations and polymer simulations indicate that narrow origins of loop extrusion favor jet formation. Unless constrained by CTCF, jets propagate symmetrically for 1-2 Mb, providing an estimate for the range of in vivo loop extrusion. Asymmetric CTCF binding deflects the angle of jet propagation as experimental evidence that cohesin-mediated loop extrusion can switch from bi- to unidirectional and is controlled independently in both directions. These data offer new insights into the physiological behavior of in vivo cohesin-mediated loop extrusion and further our understanding of the principles that underlie genome organization.

Journal article

Baranasic D, Hortenhuber M, Balwierz PJ, Zehnder T, Mukarram AK, Nepal C, Varnai C, Hadzhiev Y, Jimenez-Gonzalez A, Li N, Wragg J, D'Orazio FM, Relic D, Pachkov M, Diaz N, Hernandez-Rodriguez B, Chen Z, Stoiber M, Dong M, Stevens I, Ross SE, Eagle A, Martin R, Obasaju O, Rastegar S, McGarvey AC, Kopp W, Chambers E, Wang D, Kim HR, Acemel RD, Naranjo S, Lapinski M, Chong V, Mathavan S, Peers B, Sauka-Spengler T, Vingron M, Carninci P, Ohler U, Lacadie SA, Burgess SM, Winata C, van Eeden F, Vaquerizas JM, Luis Gomez-Skarmeta J, Onichtchouk D, Brown BJ, Bogdanovic O, van Nimwegen E, Westerfield M, Wardle FC, Daub CO, Lenhard B, Muller Fet al., 2022, Multiomic atlas with functional stratification and developmental dynamics of zebrafish <i>cis</i>-regulatory elements, NATURE GENETICS, Vol: 54, Pages: 1037-+, ISSN: 1061-4036

Journal article

Jobbins AM, Haberman N, Artigas N, Amourda C, Paterson HAB, Yu S, Blackford SJ, Montoya A, Dore M, Wang Y-F, Sardini A, Cebola I, Zuber J, Rashid ST, Lenhard B, Vernia Set al., 2022, Dysregulated RNA polyadenylation contributes to metabolic impairment in non-alcoholic fatty liver disease, Nucleic Acids Research, Vol: 50, Pages: 3379-3393, ISSN: 0305-1048

Pre-mRNA processing is an essential mechanism for the generation of mature mRNA and the regulation of gene expression in eukaryotic cells. While defects in pre-mRNA processing have been implicated in a number of diseases their involvement in metabolic pathologies is still unclear. Here, we show that both alternative splicing and alternative polyadenylation, two major steps in pre-mRNA processing, are significantly altered in non-alcoholic fatty liver disease (NAFLD). Moreover, we find that Serine and Arginine Rich Splicing Factor 10 (SRSF10) binding is enriched adjacent to consensus polyadenylation motifs and its expression is significantly decreased in NAFLD, suggesting a role mediating pre-mRNA dysregulation in this condition. Consistently, inactivation of SRSF10 in mouse and human hepatocytes in vitro, and in mouse liver in vivo, was found to dysregulate polyadenylation of key metabolic genes such as peroxisome proliferator-activated receptor alpha (PPARA) and exacerbate diet-induced metabolic dysfunction. Collectively our work implicates dysregulated pre-mRNA polyadenylation in obesity-induced liver disease and uncovers a novel role for SRSF10 in this process.

Journal article

Castro-Mondragon JA, Riudavets-Puig R, Rauluseviciute I, Lemma RB, Turchi L, Blanc-Mathieu R, Lucas J, Boddie P, Khan A, Perez NM, Fornes O, Leung TY, Aguirre A, Hammal F, Schmelter D, Baranasic D, Ballester B, Sandelin A, Lenhard B, Vandepoele K, Wasserman WW, Parcy F, Mathelier Aet al., 2022, JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles, NUCLEIC ACIDS RESEARCH, Vol: 50, Pages: D165-D173, ISSN: 0305-1048

Journal article

Lopez-Perez AR, Balwierz PJ, Lenhard B, Muller F, Wardle FC, Manfroid I, Voz ML, Peers Bet al., 2021, Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics, SCIENTIFIC REPORTS, Vol: 11, ISSN: 2045-2322

Journal article

Baranasic D, Hörtenhuber M, Balwierz P, Zehnder T, Mukarram AK, Nepal C, Varnai C, Hadzhiev Y, Jimenez-Gonzalez A, Li N, Wragg J, DOrazio F, Díaz N, Hernández-Rodríguez B, Chen Z, Stoiber M, Dong M, Stevens I, Ross SE, Eagle A, Martin R, Obasaju P, Rastegar S, McGarvey AC, Kopp W, Chambers E, Wang D, Kim HR, Acemel RD, Naranjo S, Lapinski M, Chong V, Mathavan S, Peers B, Sauka-Spengler T, Vingron M, Carninci P, Ohler U, Lacadie SA, Burgess S, Winata C, van Eeden F, Vaquerizas JM, Gómez-Skarmeta JL, Onichtchouk D, Brown BJ, Bogdanovic O, Westerfield M, Wardle FC, Daub CO, Lenhard B, Müller Fet al., 2021, Integrated annotation and analysis of genomic features reveal new types of functional elements and large-scale epigenetic phenomena in the developing zebrafish

<jats:title>Abstract</jats:title><jats:p>Zebrafish, a popular model for embryonic development and for modelling human diseases, has so far lacked a systematic functional annotation programme akin to those in other animal models. To address this, we formed the international DANIO-CODE consortium and created the first central repository to store and process zebrafish developmental functional genomic data. Our Data Coordination Center (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://danio-code.zfin.org">https://danio-code.zfin.org</jats:ext-link>) combines a total of 1,802 sets of unpublished and reanalysed published genomics data, which we used to improve existing annotations and show its utility in experimental design. We identified over 140,000 cis-regulatory elements in development, including novel classes with distinct features dependent on their activity in time and space. We delineated the distinction between regulatory elements active during zygotic genome activation and those active during organogenesis, identifying new aspects of how they relate to each other. Finally, we matched regulatory elements and epigenomic landscapes between zebrafish and mouse and predict functional relationships between them beyond sequence similarity, extending the utility of zebrafish developmental genomics to mammals.</jats:p>

Journal article

López-Pérez AR, Balwierz PJ, Lenhard B, Muller F, Wardle FC, Manfroid I, Voz ML, Peers Bet al., 2021, Identification of Downstream Effectors of Retinoic Acid Specifying the Zebrafish Pancreas by Integrative Genomics.

<jats:title>Abstract</jats:title> <jats:p>Retinoic acid (RA) is a key signal for the specification of the pancreas. Still, the gene regulatory cascade triggered by RA in the endoderm remains poorly characterized. In this study, we investigated this regulatory network in zebrafish by combining RNA-seq, RAR ChIP-seq and ATAC-seq assays. By analysing the effect of RA and of the RA receptor (RAR) antagonist BMS439 on the transcriptome and on the chromatin accessibility of endodermal cells, we identified a large set of genes and regulatory regions regulated by RA signalling. RAR ChIP-seq further defined the direct RAR target genes in zebrafish, including <jats:italic>hox</jats:italic> genes as well as several pancreatic regulators like <jats:italic>mnx1</jats:italic>, <jats:italic>insm1b</jats:italic>, <jats:italic>hnf1ba</jats:italic> and <jats:italic>gata6</jats:italic>. Comparison of zebrafish and murine RAR ChIP-seq data highlighted the conserved direct target genes and revealed that some RAR sites are under strong evolutionary constraints. Among them, a novel highly conserved RAR-induced enhancer was identified downstream of the <jats:italic>HoxB</jats:italic> locus and driving expression in the nervous system and in the gut in a RA-dependant manner. Finally, ATAC-seq data unveiled the role of the RAR-direct targets Hnf1ba and Gata6 in opening chromatin at many regulatory loci upon RA treatment.</jats:p>

Journal article

Casadio R, Lenhard B, Sternberg MJE, 2021, Computational Resources for Molecular Biology 2021, JOURNAL OF MOLECULAR BIOLOGY, Vol: 433, ISSN: 0022-2836

Journal article

Bonetti A, Agostini F, Suzuki AM, Hashimoto K, Pascarella G, Gimenez J, Roos L, Nash AJ, Ghilotti M, Cameron CJF, Valentine M, Medvedeva YA, Noguchi S, Agirre E, Kashi K, Samudyata, Luginbuehl J, Cazzoli R, Agrawal S, Luscombe NM, Blanchette M, Kasukawa T, de Hoon M, Arner E, Lenhard B, Plessy C, Castelo-Branco G, Orlando V, Carninci Pet al., 2021, RADICL-seq identifies general and cell type-specific principles of genome-wide RNA-chromatin interactions (vol 11, 1018, 2020), NATURE COMMUNICATIONS, Vol: 12, ISSN: 2041-1723

Journal article

Weiss FD, Calderon L, Wang Y-F, Georgieva R, Guo Y, Cvetesic N, Kaur M, Dharmalingam G, Krantz ID, Lenhard B, Fisher A, Merkenschlager Met al., 2021, Neuronal genes deregulated in Cornelia de Lange Syndrome respond to removal and reexpression of cohesin, Nature Communications, Vol: 12, ISSN: 2041-1723

Cornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterize the transcriptional profile of cortical neurons from CdLS patients and find deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupts 3D genome organization and transcriptional control in post-mitotic cortical mouse neurons, demonstrating that cohesin is continuously required for neuronal gene expression. The genes affected by acute depletion of cohesin belong to similar gene ontology classes and show significant numerical overlap with genes deregulated in CdLS. Interestingly, reconstitution of cohesin function largely rescues altered gene expression, including the expression of genes deregulated in CdLS.

Journal article

D'Orazio FM, Balwierz PJ, Gonzalez AJ, Guo Y, Hernandez-Rodriguez B, Wheatley L, Jasiulewicz A, Hadzhiev Y, Vaquerizas JM, Cairns B, Lenhard B, Mueller Fet al., 2021, Germ cell differentiation requires Tdrd7-dependent chromatin and transcriptome reprogramming marked by germ plasm relocalization, DEVELOPMENTAL CELL, Vol: 56, Pages: 641-+, ISSN: 1534-5807

Journal article

Beltran T, Pahita E, Ghosh S, Lenhard B, Sarkies Pet al., 2021, Integrator is recruited to promoter-proximally paused RNA Pol II to generate Caenorhabditis elegans piRNA precursors, The EMBO Journal, Vol: 40, Pages: 1-17, ISSN: 0261-4189

Piwi‐interacting RNAs (piRNAs) play key roles in germline development and genome defence in metazoans. In C. elegans, piRNAs are transcribed from > 15,000 discrete genomic loci by RNA polymerase II (Pol II), resulting in 28 nt short‐capped piRNA precursors. Here, we investigate transcription termination at piRNA loci. We show that the Integrator complex, which terminates snRNA transcription, is recruited to piRNA loci. Moreover, we demonstrate that the catalytic activity of Integrator cleaves nascent capped piRNA precursors associated with promoter‐proximal Pol II, resulting in termination of transcription. Loss of Integrator activity, however, does not result in transcriptional readthrough at the majority of piRNA loci. Taken together, our results draw new parallels between snRNA and piRNA biogenesis in nematodes and provide evidence of a role for the Integrator complex as a terminator of promoter‐proximal RNA polymerase II during piRNA biogenesis.

Journal article

Zeisig BB, Fung TK, Zarowiecki M, Tsai CT, Luo H, Stanojevic B, Lynn C, Leung AYH, Zuna J, Zaliova M, Bornhauser M, von Bonin M, Lenhard B, Huang S, Mufti GJ, So CWEet al., 2021, Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia, SCIENCE TRANSLATIONAL MEDICINE, Vol: 13, ISSN: 1946-6234

Journal article

Karimi MM, Guo Y, Cui X, Pallikonda HA, Horkova V, Dore MH, Wang Y-F, Ruiz Gil S, Rodriguez-Eteban G, Robles Rebollo I, Bruno L, Georgieva R, Patel B, Elliott J, Dauphars D, Krangel MS, Lenhard B, Heyn H, Fisher AG, Stepanek O, Merkenschlager Met al., 2021, The order and logic of CD4 CD8 lineage choice and differentiation in mouse thymus, Nature Communications, Vol: 12, ISSN: 2041-1723

CD4 and CD8 mark helper and cytotoxic T cell lineages, respectively, and serve as coreceptors for MHC-restricted TCR recognition. How coreceptor expression is matched with TCR specificity is central to understanding CD4/CD8 lineage choice, but visualising coreceptor gene activity in individual selection intermediates has been technically challenging. It therefore remains unclear whether the sequence of coreceptor gene expression in selection intermediates follows a stereotypic pattern, or is responsive to signaling. Here we use single cell RNA sequencing (scRNA-seq) to classify mouse thymocyte selection intermediates by coreceptor gene expression. In the unperturbed thymus, Cd4+Cd8a- selection intermediates appear before Cd4-Cd8a+ selection intermediates, but the timing of these subsets is flexible according to the strength of TCR signals. Our data show that selection intermediates discriminate MHC class prior to the loss of coreceptor expression and suggest a model where signal strength informs the timing of coreceptor gene activity and ultimately CD4/CD8 lineage choice.

Journal article

Yu C, Cvetesic N, Hisler V, Gupta K, Ye T, Gazdag E, Negroni L, Hajkova P, Berger I, Lenhard B, Mueller F, Vincent SD, Tora Let al., 2020, TBPL2/TFIIA complex establishes the maternal transcriptome through oocyte-specific promoter usage, Nature Communications, Vol: 11, ISSN: 2041-1723

During oocyte growth, transcription is required to create RNA and protein reserves to achieve maternal competence. During this period, the general transcription factor TATA binding protein (TBP) is replaced by its paralogue, TBPL2 (TBP2 or TRF3), which is essential for RNA polymerase II transcription. We show that in oocytes TBPL2 does not assemble into a canonical TFIID complex. Our transcript analyses demonstrate that TBPL2 mediates transcription of oocyte-expressed genes, including mRNA survey genes, as well as specific endogenous retroviral elements. Transcription start site (TSS) mapping indicates that TBPL2 has a strong preference for TATA-like motif in core promoters driving sharp TSS selection, in contrast with canonical TBP/TFIID-driven TATA-less promoters that have broader TSS architecture. Thus, we show a role for the TBPL2/TFIIA complex in the establishment of the oocyte transcriptome by using a specific TSS recognition code.

Journal article

Martin-Duran JM, Vellutini BC, Marletaz F, Cetrangolo V, Cvetesic N, Thiel D, Henriet S, Grau-Bove X, Carrillo-Baltodano AM, Gu W, Kerbl A, Marquez Y, Bekkouche N, Chourrout D, Gomez-Skarmeta JL, Irimia M, Lenhard B, Worsaae K, Hejnol Aet al., 2020, Conservative route to genome compaction in a miniature annelid (November, 10.1038/s41559-020-01327-6, 2020), Nature Ecology and Evolution, Vol: 5, Pages: 262-262, ISSN: 2397-334X

Journal article

Martin-Duran JM, Vellutini BC, Marletaz F, Cetrangolo V, Cvetesic N, Thiel D, Henriet S, Grau-Bove X, Carrillo-Baltodano AM, Gu W, Kerbl A, Marquez Y, Bekkouche N, Chourrout D, Gomez-Skarmeta JL, Irimia M, Lenhard B, Worsaae K, Hejnol Aet al., 2020, Conservative route to genome compaction in a miniature annelid, Nature Ecology and Evolution, Vol: 5, Pages: 231-242, ISSN: 2397-334X

The causes and consequences of genome reduction in animals are unclear because our understanding of this process mostly relies on lineages with often exceptionally high rates of evolution. Here, we decode the compact 73.8-megabase genome of Dimorphilus gyrociliatus, a meiobenthic segmented worm. The D. gyrociliatus genome retains traits classically associated with larger and slower-evolving genomes, such as an ordered, intact Hox cluster, a generally conserved developmental toolkit and traces of ancestral bilaterian linkage. Unlike some other animals with small genomes, the analysis of the D. gyrociliatus epigenome revealed canonical features of genome regulation, excluding the presence of operons and trans-splicing. Instead, the gene-dense D. gyrociliatus genome presents a divergent Myc pathway, a key physiological regulator of growth, proliferation and genome stability in animals. Altogether, our results uncover a conservative route to genome compaction in annelids, reminiscent of that observed in the vertebrate Takifugu rubripes.

Journal article

López-Pérez AR, Balwierz PJ, Lenhard B, Muller F, Wardle FC, Manfroid I, Voz ML, Peers Bet al., 2020, Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics

<jats:title>Abstract</jats:title><jats:p>Retinoic acid (RA) is a key signal for the specification of the pancreas. Still, the gene regulatory cascade triggered by RA in the endoderm remains poorly characterized. In this study, we investigated this regulatory network in zebrafish by combining RNA-seq, RAR ChIP-seq and ATAC-seq assays. By analysing the effect of RA and of the RA receptor (RAR) antagonist BMS439 on the transcriptome and on the chromatin accessibility of endodermal cells, we identified a large set of genes and regulatory regions regulated by RA signalling. RAR ChIP-seq further defined the direct RAR target genes including the known<jats:italic>hox</jats:italic>genes as well as several pancreatic regulators like<jats:italic>mnx1, insm1b, hnf1ba</jats:italic>and<jats:italic>gata6</jats:italic>. Comparison of our zebrafish data with available murine RAR ChIP-seq data highlighted conserved direct target genes and revealed that some RAR sites are under strong evolutionary constraints. Among them, a novel highly conserved RAR-induced enhancer was identified downstream of the<jats:italic>HoxB</jats:italic>locus and driving expression in the nervous system and in the gut in a RA-dependant manner. Finally, ATAC-seq data unveiled the role of the RAR-direct targets Hnf1ba and Gata6 in opening chromatin at many regulatory loci upon RA treatment.</jats:p><jats:sec><jats:title>Summary statement</jats:title><jats:p>Combination of RNA-seq, ChIP-seq and ATAC-seq assays identifies genes directly and indirectly regulated by RA signalling in zebrafish endoderm. Comparison with murine data highlights RAR binding sites conserved among vertebrates.</jats:p></jats:sec>

Journal article

Cvetesic N, Borkowska M, Hatanaka Y, Yu C, Vincent SD, Müller F, Tora L, Leitch HG, Hajkova P, Lenhard Bet al., 2020, Global regulatory transitions at core promoters demarcate the mammalian germline cycle

<jats:title>Abstract</jats:title><jats:p>Core promoters integrate regulatory inputs of genes<jats:sup>1–3</jats:sup>. Global dynamics of promoter usage can reveal systemic changes in how genomic sequence is interpreted by the cell<jats:sup>4</jats:sup> Here we report the first analysis of promoter dynamics and code switching in the mammalian germ line, characterising the full cycle of transitions from embryonic stem cells through germline, oogenesis, and zygotic genome activation. Using Super Low Input Carrier-CAGE<jats:sup>5,6</jats:sup> (SLIC-CAGE) we show that mouse germline development starts with the somatic promoter code, followed by a prominent switch to the maternal code during follicular oogenesis. The sequence features underlying the shift from somatic to maternal code are conserved across vertebrates, despite large differences in promoter nucleotide compositions. In addition, we show that, prior to this major shift, the promoters of gonadal germ cells diverge from the canonical somatic transcription initiation. This divergence is distinct from the promoter code used later by developing oocytes and reveals genome-wide promoter remodelling associated with alternative nucleosome positioning during early female and male germline development. Collectively, our findings establish promoter-level regulatory transitions as a central, conserved feature of the vertebrate life cycle.</jats:p>

Journal article

Wragg JW, Roos L, Vucenovic D, Cvetesic N, Lenhard B, Mueller Fet al., 2020, Embryonic tissue differentiation is characterized by transitions in cell cycle dynamic-associated core promoter regulation, NUCLEIC ACIDS RESEARCH, Vol: 48, Pages: 8374-8392, ISSN: 0305-1048

Journal article

Ramilowski JA, Yip CW, Agrawal S, Chang J-C, Ciani Y, Kulakovskiy IV, Mendez M, Ooi JLC, Ouyang JF, Parkinson N, Petri A, Roos L, Severin J, Yasuzawa K, Abugessaisa I, Akalin A, Antonov IV, Arner E, Bonetti A, Bono H, Borsari B, Brombacher F, Cameron CJF, Cannistraci CV, Cardenas R, Cardon M, Chang H, Dostie J, Ducoli L, Favorov A, Fort A, Garrido D, Gil N, Gimenez J, Guler R, Handoko L, Harshbarger J, Hasegawa A, Hasegawa Y, Hashimoto K, Hayatsu N, Heutink P, Hirose T, Imada EL, Itoh M, Kaczkowski B, Kanhere A, Kawabata E, Kawaji H, Kawashima T, Kelly ST, Kojima M, Kondo N, Koseki H, Kouno T, Kratz A, Kurowska-Stolarska M, Kwon ATJ, Leek J, Lennartsson A, Lizio M, Lopez-Redondo F, Luginbuhl J, Maeda S, Makeev VJ, Marchionni L, Medvedeva YA, Minoda A, Muller F, Munoz-Aguirre M, Murata M, Nishiyori H, Nitta KR, Noguchi S, Noro Y, Nurtdinov R, Okazaki Y, Orlando V, Paquette D, Parr CJC, Rackham OJL, Rizzu P, Martinez DFS, Sandelin A, Sanjana P, Semple CAM, Shibayama Y, Sivaraman DM, Suzuki T, Szumowski SC, Tagami M, Taylor MS, Terao C, Thodberg M, Thongjuea S, Tripathi V, Ulitsky I, Verardo R, Vorontsov IE, Yamamoto C, Young RS, Baillie JK, Forrest ARR, Guigo R, Hoffman MM, Hon CC, Kasukawa T, Kauppinen S, Kere J, Lenhard B, Schneider C, Suzuki H, Yagi K, de Hoon MJL, Shin JW, Carninci Pet al., 2020, Functional annotation of human long noncoding RNAs via molecular phenotyping (vol 30, pg 1060, 2020), Genome Research, Vol: 30, Pages: 1377-1377, ISSN: 1054-9803

Journal article

Lopez-Noriega L, Callingham R, Martinez-Sánchez A, Nawaz S, Pizza G, Haberman N, Cvetesic N, Nguyen-Tu M-S, Lenhard B, Marchetti P, Piemonti L, de Koning E, Shapiro AMJ, Johnson PR, Leclerc I, Hastoy B, Gauthier BR, Pullen TJ, Rutter GAet al., 2020, Roles for the long non-coding RNA<i>Pax6os1</i>/<i>PAX6-AS1</i>in pancreatic beta cell identity and function

<jats:title>Abstract</jats:title><jats:sec><jats:title>Aim/Hypothesis</jats:title><jats:p>Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of beta cell development and function. Here, we investigate roles for an antisense lncRNA expressed from the<jats:italic>Pax6</jats:italic>locus (annotated as<jats:italic>Pax6os1</jats:italic>in mice and<jats:italic>PAX6-AS1</jats:italic>in humans) in beta cell identity and functionality.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p><jats:italic>Pax6os1</jats:italic>expression was silenced in MIN6 cells using siRNAs and changes in gene expression were determined by RNA sequencing or qRT-PCR. Mice inactivated for<jats:italic>Pax6os1</jats:italic>and human<jats:italic>PAX6-AS1</jats:italic>-null EndoC-βH1 cells, were generated using CRISPR/Cas9 technology. Human islets were infected with lentiviral vectors bearing a targeted shRNA or<jats:italic>PAX6-AS1</jats:italic>, which were used to silence or overexpress, respectively, the lncRNA. RNA sequencing or RT-qPCR were used to measure transcriptomic changes and RNA pulldown in mice and human cells followed by mass spectrometry/western blot were performed to explore RNA protein interactions.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p><jats:italic>Pax6os1/PAX6-AS1</jats:italic>expression was upregulated at high glucose concentrations in derived beta cell lines as well as in mouse and human islets, and in pancreatic islets isolated from mice fed a high fat diet (n=6, p=0.003) and patients with type 2 diabetes (n=11-5, p&lt;0.01). Silencing or deletion of<jats:italic>Pax6os1</jats:italic>/<jats:italic>PAX6-AS1</jats:italic>in MIN6 or EndoC-βH1cells increased the expression of several

Journal article

Ramilowski JA, Yip CW, Agrawal S, Chang J-C, Ciani Y, Kulakovskiy IV, Mendez M, Ooi JLC, Ouyang JF, Parkinson N, Petri A, Roos L, Severin J, Yasuzawa K, Abugessaisa I, Akalin A, Antonov IV, Arner E, Bonetti A, Bono H, Borsari B, Brombacher F, Cameron CJF, Cannistraci CV, Cardenas R, Cardon M, Chang H, Dostie J, Ducoli L, Favorov A, Fort A, Garrido D, Gil N, Gimenez J, Guler R, Handoko L, Harshbarger J, Hasegawa A, Hasegawa Y, Hashimoto K, Hayatsu N, Heutink P, Hirose T, Imada EL, Itoh M, Kaczkowski B, Kanhere A, Kawabata E, Kawaji H, Kawashima T, Kelly ST, Kojima M, Kondo N, Koseki H, Kouno T, Kratz A, Kurowska-Stolarska M, Kwon ATJ, Leek J, Lennartsson A, Lizio M, Lopez-Redondo F, Luginbuhl J, Maeda S, Makeev VJ, Marchionni L, Medvedeva YA, Minoda A, Mueller F, Munoz-Aguirre M, Murata M, Nishiyori H, Nitta KR, Noguchi S, Noro Y, Nurtdinov R, Okazaki Y, Orlando V, Paquette D, Parr CJC, Rackham OJL, Rizzu P, Martinez DFS, Sandelin A, Sanjana P, Semple CAM, Shibayama Y, Sivaraman DM, Suzuki T, Szumowski SC, Tagami M, Taylor MS, Terao C, Thodberg M, Thongjuea S, Tripathi V, Ulitsky I, Verardo R, Vorontsov IE, Yamamoto C, Young RS, Baillie JK, Forrest ARR, Guigo R, Hoffman MM, Hon CC, Kasukawa T, Kauppinen S, Kere J, Lenhard B, Schneider C, Suzuki H, Yagi K, de Hoon MJL, Shin JW, Carninci Pet al., 2020, Functional annotation of human long noncoding RNAs via molecular phenotyping, Genome Research, Vol: 30, Pages: 1060-1072, ISSN: 1054-9803

Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-to-date lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.

Journal article

Yu C, Cvetesic N, Hisler V, Gupta K, Ye T, Gazdag E, Negroni L, Hajkova P, Berger I, Lenhard B, Müller F, Vincent SD, Tora Let al., 2020, TBPL2/TFIIA complex establishes the maternal transcriptome by an oocyte-specific promoter usage

<jats:title>Abstract</jats:title><jats:p>During oocyte growth, transcription is required to create RNA and protein reserves to achieve maternal competence. During this period, the general transcription factor TATA binding protein (TBP) is replaced by its paralogue, TBPL2 (TBP2 or TRF3), which is essential for RNA polymerase II transcription. We show that in oocytes TBPL2 does not assemble into a canonical TFIID complex. Our transcript analyses demonstrate that TBPL2 mediates transcription of oocyte-expressed genes, including mRNA survey genes, as well as specific endogenous retroviral elements. Transcription start site (TSS) mapping indicates that TBPL2 has a strong preference for TATA-like motif in core promoters driving sharp TSS selection, in contrast with canonical TBP/TFIID-driven TATA-less promoters that have broader TSS architecture. Thus, we show a role for the TBPL2/TFIIA complex in the establishment of the oocyte transcriptome by using a specific TSS recognition code.</jats:p>

Journal article

Weiss FD, Calderon L, Wang Y-F, Georgieva R, Guo Y, Cvetesic N, Kaur M, Dharmalingam G, Krantz ID, Lenhard B, Fisher AG, Merkenschlager Met al., 2020, Partial rescue of neuronal genes deregulated in Cornelia de Lange Syndrome by cohesin

<jats:title>Abstract</jats:title><jats:p>Cornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterized the transcriptional profile of cortical neurons from CdLS patients and found deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupted 3-D genome organization and transcriptional control in post-mitotic cortical mouse neurons. The genes affected belonged to similar gene ontology classes and showed significant numerical overlap with those deregulated in CdLS. Interestingly, gene expression was largely rescued by subsequent reconstitution of cohesin function. These experiments show that cohesin is continuously required for neuronal gene expression and provide a tractable approach for addressing mechanisms of neuronal dysfunction in CdLS.</jats:p>

Journal article

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