Imperial College London

ProfessorBorisLenhard

Faculty of MedicineInstitute of Clinical Sciences

Professor of Computational Biology
 
 
 
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Contact

 

+44 (0)20 3313 8353b.lenhard Website

 
 
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Assistant

 

Ms Yvonne Aftyka +44 (0)20 3313 4318

 
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Location

 

230ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

123 results found

Cantone I, Dharmalingam G, Chan YW, Kohler AC, Lenhard B, Merkenschlager M, Fisher AGet al., 2017, Allele-specific analysis of cell fusion-mediated pluripotent reprograming reveals distinct and predictive susceptibilities of human X-linked genes to reactivation., Genome Biol, Vol: 18

BACKGROUND: Inactivation of one X chromosome is established early in female mammalian development and can be reversed in vivo and in vitro when pluripotency factors are re-expressed. The extent of reactivation along the inactive X chromosome (Xi) and the determinants of locus susceptibility are, however, poorly understood. Here we use cell fusion-mediated pluripotent reprograming to study human Xi reactivation and allele-specific single nucleotide polymorphisms (SNPs) to identify reactivated loci. RESULTS: We show that a subset of human Xi genes is rapidly reactivated upon re-expression of the pluripotency network. These genes lie within the most evolutionary recent segments of the human X chromosome that are depleted of LINE1 and enriched for SINE elements, predicted to impair XIST spreading. Interestingly, this cadre of genes displays stochastic Xi expression in human fibroblasts ahead of reprograming. This stochastic variability is evident between clones, by RNA-sequencing, and at the single-cell level, by RNA-FISH, and is not attributable to differences in repressive histone H3K9me3 or H3K27me3 levels. Treatment with the DNA demethylating agent 5-deoxy-azacytidine does not increase Xi expression ahead of reprograming, but instead reveals a second cadre of genes that only become susceptible to reactivation upon induction of pluripotency. CONCLUSIONS: Collectively, these data not only underscore the multiple pathways that contribute to maintaining silencing along the human Xi chromosome but also suggest that transcriptional stochasticity among human cells could be useful for predicting and engineering epigenetic strategies to achieve locus-specific or domain-specific human Xi gene reactivation.

JOURNAL ARTICLE

Cvetesic N, Lenhard B, 2017, Core promoters across the genome., Nat Biotechnol, Vol: 35, Pages: 123-124

JOURNAL ARTICLE

Cheung N, Fung TK, Zeisig BB, Holmes K, Rane JK, Mowen KA, Finn MG, Lenhard B, Chan LC, So CWEet al., 2016, Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia, CANCER CELL, Vol: 29, Pages: 32-48, ISSN: 1535-6108

JOURNAL ARTICLE

Cvetesic N, Dulic M, Bilus M, Sostaric N, Lenhard B, Gruic-Sovulj Iet al., 2016, Naturally Occurring Isoleucyl-tRNA Synthetase without tRNA-dependent Pre-transfer Editing, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 291, Pages: 8618-8631, ISSN: 0021-9258

JOURNAL ARTICLE

Haberle V, Lenhard B, 2016, Promoter architectures and developmental gene regulation, SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, Vol: 57, Pages: 11-23, ISSN: 1084-9521

JOURNAL ARTICLE

Kolder ICRM, van der Plas-Duivesteijn SJ, Tan G, Wiegertjes GF, Forlenza M, Guler AT, Travin DY, Nakao M, Moritomo T, Irnazarow I, den Dunnen JT, Anvar SY, Jansen HJ, Dirks RP, Palmblad M, Lenhard B, Henkel CV, Spaink HPet al., 2016, A full-body transcriptome and proteome resource for the European common carp, BMC GENOMICS, Vol: 17, ISSN: 1471-2164

JOURNAL ARTICLE

Mathelier A, Fornes O, Arenillas DJ, Chen C-Y, Denay G, Lee J, Shi W, Shyr C, Tan G, Worsley-Hunt R, Zhang AW, Parcy F, Lenhard B, Sandelin A, Wasserman WWet al., 2016, JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles, NUCLEIC ACIDS RESEARCH, Vol: 44, Pages: D110-D115, ISSN: 0305-1048

JOURNAL ARTICLE

Nepal C, Coolen M, Hadzhiev Y, Cussigh D, Mydel P, Steen VM, Carninci P, Andersen JB, Bally-Cuif L, Muller F, Lenhard Bet al., 2016, Transcriptional, post-transcriptional and chromatin-associated regulation of pri-miRNAs, pre-miRNAs and moRNAs, NUCLEIC ACIDS RESEARCH, Vol: 44, Pages: 3070-3081, ISSN: 0305-1048

JOURNAL ARTICLE

Tan G, Lenhard B, 2016, TFBSTools: an R/bioconductor package for transcription factor binding site analysis, BIOINFORMATICS, Vol: 32, Pages: 1555-1556, ISSN: 1367-4803

JOURNAL ARTICLE

Adlakha AG, Armstrong-James DPH, Lenhard B, 2015, CALCINEURIN INHIBITION IMPAIRS PHENOTYPIC MATURATION OF DENDRITIC CELLS IN A IN VITRO MODEL OF INVASIVE ASPERGILLOSIS IN LUNG TRANSPLANT RECIPIENTS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A48-A49, ISSN: 0040-6376

CONFERENCE PAPER

Danks GB, Raasholm M, Campsteijn C, Long AM, Manak JR, Lenhard B, Thompson EMet al., 2015, Trans-Splicing and Operons in Metazoans: Translational Control in Maternally Regulated Development and Recovery from Growth Arrest, MOLECULAR BIOLOGY AND EVOLUTION, Vol: 32, Pages: 585-599, ISSN: 0737-4038

JOURNAL ARTICLE

Haberle V, Forrest ARR, Hayashizaki Y, Carninci P, Lenhard Bet al., 2015, CAGEr: precise TSS data retrieval and high-resolution promoterome mining for integrative analyses, NUCLEIC ACIDS RESEARCH, Vol: 43, ISSN: 0305-1048

JOURNAL ARTICLE

Harmston N, Ing-Simmons E, Perry M, Baresic A, Lenhard Bet al., 2015, GenomicInteractions: An R/Bioconductor package for manipulating and investigating chromatin interaction data, BMC GENOMICS, Vol: 16, ISSN: 1471-2164

JOURNAL ARTICLE

Ing-Simmons E, Seitan VC, Faure AJ, Flicek P, Carroll T, Dekker J, Fisher AG, Lenhard B, Merkenschlager Met al., 2015, Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin, GENOME RESEARCH, Vol: 25, Pages: 504-513, ISSN: 1088-9051

JOURNAL ARTICLE

Ishibashi M, Manning E, Shoubridge C, Krecsmarik M, Hawkins TA, Giacomotto J, Zhao T, Mueller T, Bader PI, Cheung SW, Stankiewicz P, Bain NL, Hackett A, Reddy CCS, Mechaly AS, Peers B, Wilson SW, Lenhard B, Bally-Cuif L, Gecz J, Becker TS, Rinkwitz Set al., 2015, Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene, HUMAN GENETICS, Vol: 134, Pages: 1163-1182, ISSN: 0340-6717

JOURNAL ARTICLE

Naville M, Ishibashi M, Ferg M, Bengani H, Rinkwitz S, Krecsmarik M, Hawkins TA, Wilson SW, Manning E, Chilamakuri CSR, Wilson DI, Louis A, Raymond FL, Rastegar S, Straehle U, Lenhard B, Bally-Cuif L, van Heyningen V, FitzPatrick DR, Becker TS, Crollius HRet al., 2015, Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome, NATURE COMMUNICATIONS, Vol: 6, ISSN: 2041-1723

JOURNAL ARTICLE

Stadhouders R, Cico A, Stephen T, Thongjuea S, Kolovos P, Baymaz HI, Yu X, Demmers J, Bezstarosti K, Maas A, Barroca V, Kockx C, Ozgur Z, van Ijcken W, Arcangeli M-L, Andrieu-Soler C, Lenhard B, Grosveld F, Soler Eet al., 2015, Control of developmentally primed erythroid genes by combinatorial co-repressor actions, NATURE COMMUNICATIONS, Vol: 6, ISSN: 2041-1723

JOURNAL ARTICLE

Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, Chen Y, Zhao X, Schmidl C, Suzuki T, Ntini E, Arner E, Valen E, Li K, Schwarzfischer L, Glatz D, Raithel J, Lilje B, Rapin N, Bagger FO, Jørgensen M, Andersen PR, Bertin N, Rackham O, Burroughs AM, Baillie JK, Ishizu Y, Shimizu Y, Furuhata E, Maeda S, Negishi Y, Mungall CJ, Meehan TF, Lassmann T, Itoh M, Kawaji H, Kondo N, Kawai J, Lennartsson A, Daub CO, Heutink P, Hume DA, Jensen TH, Suzuki H, Hayashizaki Y, Müller F, FANTOM Consortium, Forrest AR, Carninci P, Rehli M, Sandelin Aet al., 2014, An atlas of active enhancers across human cell types and tissues., Nature, Vol: 507, Pages: 455-461

Enhancers control the correct temporal and cell-type-specific activation of gene expression in multicellular eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. Here we use the FANTOM5 panel of samples, covering the majority of human tissues and cell types, to produce an atlas of active, in vivo-transcribed enhancers. We show that enhancers share properties with CpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell-type-specific enhancers and gene regulation.

JOURNAL ARTICLE

Forrest ARR, Kawaji H, Rehli M, Baillie JK, de Hoon MJL, Haberle V, Lassmann T, Kulakovskiy IV, Lizio M, Itoh M, Andersson R, Mungall CJ, Meehan TF, Schmeier S, Bertin N, Jorgensen M, Dimont E, Arner E, Schmidl C, Schaefer U, Medvedeva YA, Plessy C, Vitezic M, Severin J, Semple CA, Ishizu Y, Young RS, Francescatto M, Alam I, Albanese D, Altschuler GM, Arakawa T, Archer JAC, Arner P, Babina M, Rennie S, Balwierz PJ, Beckhouse AG, Pradhan-Bhatt S, Blake JA, Blumenthal A, Bodega B, Bonetti A, Briggs J, Brombacher F, Burroughs AM, Califano A, Cannistraci CV, Carbajo D, Chen Y, Chierici M, Ciani Y, Clevers HC, Dalla E, Davis CA, Detmar M, Diehl AD, Dohi T, Drablos F, Edge ASB, Edinger M, Ekwall K, Endoh M, Enomoto H, Fagiolini M, Fairbairn L, Fang H, Farach-Carson MC, Faulkner GJ, Favorov AV, Fisher ME, Frith MC, Fujita R, Fukuda S, Furlanello C, Furuno M, Furusawa J-I, Geijtenbeek TB, Gibson AP, Gingeras T, Goldowitz D, Gough J, Guhl S, Guler R, Gustincich S, Ha TJ, Hamaguchi M, Hara M, Harbers M, Harshbarger J, Hasegawa A, Hasegawa Y, Hashimoto T, Herlyn M, Hitchens KJ, Sui SJH, Hofmann OM, Hoof I, Hori F, Huminiecki L, Iida K, Ikawa T, Jankovic BR, Jia H, Joshi A, Jurman G, Kaczkowski B, Kai C, Kaida K, Kaiho A, Kajiyama K, Kanamori-Katayama M, Kasianov A, Kasukawa T, Katayama S, Kato S, Kawaguchi S, Kawamoto H, Kawamura YI, Kawashima T, Kempfle JS, Kenna TJ, Kere J, Khachigian LM, Kitamura T, Klinken SP, Knox AJ, Kojima M, Kojima S, Kondo N, Koseki H, Koyasu S, Krampitz S, Kubosaki A, Kwon AT, Laros JFJ, Lee W, Lennartsson A, Li K, Lilje B, Lipovich L, Mackay-sim A, Manabe R-I, Mar JC, Marchand B, Mathelier A, Mejhert N, Meynert A, Mizuno Y, Morais DADL, Morikawa H, Morimoto M, Moro K, Motakis E, Motohashi H, Mummery CL, Murata M, Nagao-Sato S, Nakachi Y, Nakahara F, Nakamura T, Nakamura Y, Nakazato K, Van Nimwegen E, Ninomiya N, Nishiyori H, Noma S, Nozaki T, Ogishima S, Ohkura N, Ohmiya H, Ohno H, Ohshima M, Okada-Hatakeyama M, Okazaki Y, Orlando V, Ovchinnikov DAet al., 2014, A promoter-level mammalian expression atlas, NATURE, Vol: 507, Pages: 462-+, ISSN: 0028-0836

JOURNAL ARTICLE

Haberle V, Li N, Hadzhiev Y, Plessy C, Previti C, Nepal C, Gehrig J, Dong X, Akalin A, Suzuki AM, van IJcken WFJ, Armant O, Ferg M, Straehle U, Carninci P, Mueller F, Lenhard Bet al., 2014, Two independent transcription initiation codes overlap on vertebrate core promoters, NATURE, Vol: 507, Pages: 381-+, ISSN: 0028-0836

JOURNAL ARTICLE

Mathelier A, Zhao X, Zhang AW, Parcy F, Worsley-Hunt R, Arenillas DJ, Buchman S, Chen C-Y, Chou A, Ienasescu H, Lim J, Shyr C, Tan G, Zhou M, Lenhard B, Sandelin A, Wasserman WWet al., 2014, JASPAR 2014: an extensively expanded and updated open-access database of transcription factor binding profiles, NUCLEIC ACIDS RESEARCH, Vol: 42, Pages: D142-D147, ISSN: 0305-1048

JOURNAL ARTICLE

Pascarella G, Lazarevic D, Plessy C, Bertin N, Akalin A, Vlachouli C, Simone R, Faulkner GJ, Zucchelli S, Kawai J, Daub CO, Hayashizaki Y, Lenhard B, Carninci P, Gustincich Set al., 2014, NanoCAGE analysis of the mouse olfactory epithelium identifies the expression of vomeronasal receptors and of proximal LINE elements., Front Cell Neurosci, Vol: 8

By coupling laser capture microdissection to nanoCAGE technology and next-generation sequencing we have identified the genome-wide collection of active promoters in the mouse Main Olfactory Epithelium (MOE). Transcription start sites (TSSs) for the large majority of Olfactory Receptors (ORs) have been previously mapped increasing our understanding of their promoter architecture. Here we show that in our nanoCAGE libraries of the mouse MOE we detect a large number of tags mapped in loci hosting Type-1 and Type-2 Vomeronasal Receptors genes (V1Rs and V2Rs). These loci also show a massive expression of Long Interspersed Nuclear Elements (LINEs). We have validated the expression of selected receptors detected by nanoCAGE with in situ hybridization, RT-PCR and qRT-PCR. This work extends the repertory of receptors capable of sensing chemical signals in the MOE, suggesting intriguing interplays between MOE and VNO for pheromone processing and positioning transcribed LINEs as candidate regulatory RNAs for VRs expression.

JOURNAL ARTICLE

Sharma Y, Chilamakuri CSR, Bakke M, Lenhard Bet al., 2014, Computational Characterization of Modes of Transcriptional Regulation of Nuclear Receptor Genes, PLOS ONE, Vol: 9, ISSN: 1932-6203

JOURNAL ARTICLE

Stadhouders R, Aktuna S, Thongjuea S, Aghajanirefah A, Pourfarzad F, van IJcken W, Lenhard B, Rooks H, Best S, Menzel S, Grosveld F, Thein SL, Soler Eet al., 2014, HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers, JOURNAL OF CLINICAL INVESTIGATION, Vol: 124, Pages: 1699-1710, ISSN: 0021-9738

JOURNAL ARTICLE

Zuin J, Franke V, van Ijcken WF, van der Sloot A, Krantz ID, van der Reijden MI, Nakato R, Lenhard B, Wendt KSet al., 2014, A cohesin-independent role for NIPBL at promoters provides insights in CdLS., PLoS Genet, Vol: 10

The cohesin complex is crucial for chromosome segregation during mitosis and has recently also been implicated in transcriptional regulation and chromatin architecture. The NIPBL protein is required for the loading of cohesin onto chromatin, but how and where cohesin is loaded in vertebrate cells is unclear. Heterozygous mutations of NIPBL were found in 50% of the cases of Cornelia de Lange Syndrome (CdLS), a human developmental syndrome with a complex phenotype. However, no defects in the mitotic function of cohesin have been observed so far and the links between NIPBL mutations and the observed developmental defects are unclear. We show that NIPBL binds to chromatin in somatic cells with a different timing than cohesin. Further, we observe that high-affinity NIPBL binding sites localize to different regions than cohesin and almost exclusively to the promoters of active genes. NIPBL or cohesin knockdown reduce transcription of these genes differently, suggesting a cohesin-independent role of NIPBL for transcription. Motif analysis and comparison to published data show that NIPBL co-localizes with a specific set of other transcription factors. In cells derived from CdLS patients NIPBL binding levels are reduced and several of the NIPBL-bound genes have previously been observed to be mis-expressed in CdLS. In summary, our observations indicate that NIPBL mutations might cause developmental defects in different ways. First, defects of NIPBL might lead to cohesin-loading defects and thereby alter gene expression and second, NIPBL deficiency might affect genes directly via its role at the respective promoters.

JOURNAL ARTICLE

Armant O, März M, Schmidt R, Ferg M, Diotel N, Ertzer R, Bryne JC, Yang L, Baader I, Reischl M, Legradi J, Mikut R, Stemple D, van IJcken W, van der Sloot A, Lenhard B, Strähle U, Rastegar Set al., 2013, Genome-wide, whole mount in situ analysis of transcriptional regulators in zebrafish embryos., Dev Biol, Vol: 380, Pages: 351-362

Transcription is the primary step in the retrieval of genetic information. A substantial proportion of the protein repertoire of each organism consists of transcriptional regulators (TRs). It is believed that the differential expression and combinatorial action of these TRs is essential for vertebrate development and body homeostasis. We mined the zebrafish genome exhaustively for genes encoding TRs and determined their expression in the zebrafish embryo by sequencing to saturation and in situ hybridisation. At the evolutionary conserved phylotypic stage, 75% of the 3302 TR genes encoded in the genome are already expressed. The number of expressed TR genes increases only marginally in subsequent stages and is maintained during adulthood suggesting important roles of the TR genes in body homeostasis. Fewer than half of the TR genes (45%, n=1711 genes) are expressed in a tissue-restricted manner in the embryo. Transcripts of 207 genes were detected in a single tissue in the 24h embryo, potentially acting as regulators of specific processes. Other TR genes were expressed in multiple tissues. However, with the exception of certain territories in the nervous system, we did not find significant synexpression suggesting that most tissue-restricted TRs act in a freely combinatorial fashion. Our data indicate that elaboration of body pattern and function from the phylotypic stage onward relies mostly on redeployment of TRs and post-transcriptional processes.

JOURNAL ARTICLE

Carvalho RH, Hou J, Haberle V, Aerts J, Grosveld F, Lenhard B, Philipsen Set al., 2013, Genomewide DNA methylation analysis identifies novel methylated genes in non-small-cell lung carcinomas., J Thorac Oncol, Vol: 8, Pages: 562-573

INTRODUCTION: DNA methylation is part of the epigenetic regulatory mechanism present in all normal cells. It is tissue-specific and stably maintained throughout development, but often abnormally changed in cancer. Non-small-cell lung carcinoma (NSCLC) is the most deadly type of cancer, involving different tumor subtypes. This heterogeneity is a challenge for correct diagnosis and patient treatment. The stability and specificity make of DNA methylation a very suitable marker for epigenetic phenotyping of tumors. METHODS: To identify candidate markers for use in NSCLC diagnosis, we used genomewide DNA methylation maps that we had previously generated by MethylCap and next-generation sequencing and listed the most significant differentially methylated regions (DMRs). The 25 DMRs with highest significance in their methylation scores were selected. The methylation status of these DMRs was investigated in 61 tumors and matching control lung tissues by methylation-specific polymerase chain reaction. RESULTS: We found 12 novel DMRs that showed significant differences between tumor and control lung tissues. We also identified three novel DMRs for each of the two most common NSCLC subtypes, adenocarcinomas and squamous cell carcinomas. We propose a panel of five DMRs, composed of novel and known markers that exhibit high specificity and sensitivity to distinguish tumors from control lung tissues. CONCLUSION: Novel markers will aid the development of a highly specific epigenetic panel for accurate identification and subtyping of NSCLC tumors.

JOURNAL ARTICLE

Danks G, Campsteijn C, Parida M, Butcher S, Doddapaneni H, Fu B, Petrin R, Metpally R, Lenhard B, Wincker P, Chourrout D, Thompson EM, Manak JRet al., 2013, OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica, NUCLEIC ACIDS RESEARCH, Vol: 41, Pages: D845-D853, ISSN: 0305-1048

JOURNAL ARTICLE

Frangini A, Sjoeberg M, Roman-Trufero M, Dharmalingam G, Haberle V, Bartke T, Lenhard B, Malumbres M, Vidal M, Dillon Net al., 2013, The Aurora B Kinase and the Polycomb Protein Ring1B Combine to Regulate Active Promoters in Quiescent Lymphocytes, MOLECULAR CELL, Vol: 51, Pages: 647-661, ISSN: 1097-2765

JOURNAL ARTICLE

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