Computational Regulatory Genomics

“Our research investigates how regulatory information is encoded in DNA, how it is interpreted and how it is communicated across cells in multicellular organisms”

The development of complex organisms critically depends upon regulation of gene activity across dozens, hundreds or millions of cells in time and space. This regulation ensures the fidelity of development of complex structures and the overall function of the organism. Its disruption therefore often leads to disease.

We study gene regulation at the genome-wide level using computational genomics and epigenomics, as well as experimental transcriptomics and promoter activity mapping. Our major research interests focus on:

  • Structure and function of gene promoters
  • Function and genomic distribution of gene regulatory elements
  • Function of transcription factors
  • Regulation of the production of transcription factors i.e. transcriptional regulatory networks (TRNs)
  • Association of different modes of regulation with epigenetic marks and their inheritance
  • Transcriptional and translational regulation and dynamics in embryonic development
  • The role of core promoters and their diverse architectures in vertebrate development and differentiation
  • Emergence and evolutionary dynamics of conserved non-coding elements

Our recent work centres on the functional classification of core promoters, the development of methods to correctly assign regulatory elements to the genes they regulate, and the role of the epigenome in guiding development.  Most of our work until now has been purely computational, either analysing publicly available data or in collaboration with experimental laboratories using high-throughput sequencing techniques such as CAGE, ATAC-seq, MNase-seq, RNA-seq, ChIP-seq and Hi-C. Since 2016 we also have experimental activity focusing on studying functional diversity of promoters in development and differentiation.

The boundaries of GRBs are highly consistent regardless of the thresholds or species involved (doi:10.1038/s41467-017-00524-5).

Hosting several web services and databases such as:

Jaspar

Ancora

Part of consortia

FANTOM

DANIO-CODE

Selected Publications

Khan, A., Fornes, O., Stigliani, A., Gheorghe, M., Castro-Mondragon, J. A., van der Lee, R., Bessy, A., Chèneby, J., Kulkarni, S. R., Tan, G., Baranasic, D., Arenillas, D. J., Sandelin, A., Vandepoele, K., Lenhard, B., Ballester, B., Wasserman, W. W., Parcy, F., Mathelier, A. (2017). JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web frameworkNucleic acids research, 46(D1), D260-D266.

 

Harmston, N., Ing-Simmons, E., Tan, G., Perry, M., Merkenschlager, M., & Lenhard, B. (2017). Topologically associating domains are ancient features that coincide with Metazoan clusters of extreme noncoding conservationNature communications, 8(1), 441.

Polychronopoulos, D., King, J. W., Nash, A. J., Tan, G., & Lenhard, B. (2017). Conserved non-coding elements: developmental gene regulation meets genome organizationNucleic acids research, 45(22), 12611-12624.

Cvetesic, N., & Lenhard, B. (2017). Core promoters across the genomeNature biotechnology, 35(2), 123.

Haberle V, Forrest AR, Hayashizaki Y, Carninci P, Lenhard B (2015), CAGEr: precise TSS data retrieval and high-resolution promoterome mining for integrative analyses, Nucleic Acids Res: pii: gkv054. [Epub ahead of print]

Ing-Simmons E, Seitan VC, Faure AJ, Flicek P, Carroll T, Dekker J, Fisher AG, Lenhard B, Merkenschlager M (2015), Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin, Genome Res [Epub ahead of print]

FANTOM Consortium and the RIKEN PMI and CLST (DGT), Alistair R. R. Forrest, Hideya Kawaji, Michael Rehli, J. Kenneth Baillie, Michiel J. L. de Hoon, Vanja Haberle, Timo Lassman, Ivan V. Kulakovskiy, Marina Lizio, et al (2014), A promoter-level mammalian expression atlas, Nature, 507(7493): 462–470. doi: 10.1038/nature13182

Haberle, V., Li, N., Hadzhiev, Y., Plessy, C., Previti, C., Nepal, C., Gehrig, J., Dong, X., Akalin, A., Suzuki, A. M., van IJcken, W. F. J., Armant, O., Ferg, M., Strahle, U., Carninci, P., Muller, F., & Lenhard, B. (2014). Two independent transcription initiation codes overlap on vertebrate core promoters. Nature, 507(7492), 381–385.

Zuin, J., Franke, V., van Ijcken, W. F., van der Sloot, A., Krantz, I. D., van der Reijden, M. I., Nakato, R., Lenhard, B., & Wendt, K. S. (2014). A Cohesin-Independent role for NIPBL at promoters provides insights in CdLS. PLoS Genetics, 10(2).

Thongjuea, S., Stadhouders, R., Grosveld, F. G., Soler, E., & Lenhard, B. (2013). r3Cseq: an R/Bioconductor package for the discovery of long-range genomic interactions from chromosome conformation capture and next-generation sequencing data. Nucleic Acids Research, 41(13), e132.

Lenhard, B., Sandelin, A., & Carninci, P. (2012). Metazoan promoters: emerging characteristics and insights into transcriptional regulation. Nature Reviews Genetics, 13(4), 233–245.

Soler, E., Andrieu-Soler, C., de Boer, E., Bryne, J. C. C., Thongjuea, S., Stadhouders, R., Palstra, R.-J. J., Stevens, M., Kockx, C., van Ijcken, W., Hou, J., Steinhoff, C., Rijkers, E., Lenhard, B., & Grosveld, F. (2010). The genome-wide dynamics of the binding of ldb1 complexes during erythroid differentiation. Genes & Development, 24(3), 277–289.

Ragvin, A., Moro, E., Fredman, D., Navratilova, P., Drivenes, Ø., Engström, P. G., Alonso, M. E., de la Calle Mustienes, E., Skarmeta, J. L. G., Tavares, M. J., Casares, F., Manzanares, M., van Heyningen, V., Molven, A., Njølstad, P. R., Argenton, F., Lenhard, B., & Becker, T. S. (2010). Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3. Proceedings of the National Academy of Sciences, 107(2), 775–780.

Akalin, A., Fredman, D., Arner, E., Dong, X., Bryne, J., Suzuki, H., Daub, C., Hayashizaki, Y., & Lenhard, B. (2009). Transcriptional features of genomic regulatory blocks. Genome Biology, 10(4), R38+.