Regulatory Genomics and Systems Biology

News & updates

Alternative splicing of intrinsically disordered regions and rewiring of protein interactions

Alternatively spliced protein segments tend to be intrinsically disordered and contain linear interaction motifs and/or post-translational modification sites. An emerging concept is that differential inclusion of such disordered segments can mediate new protein interactions, and hence change the context in which the biochemical or molecular functions are carried out by the protein. Since genes with disordered regions are enriched in regulatory and signaling functions, the resulting protein isoforms could alter their function in different tissues and organisms by rewiring interaction networks through the recruitment of distinct interaction partners via the alternatively spliced disordered segments. In this manner, the alternative splicing of mRNA coding for disordered segments may contribute to the emergence of new traits during evolution, development and disease. The paper by Marija Buljan et al can be found here.


Molecular signatures of G-protein-coupled receptors published in Nature

In this work, we objectively compare known structures and reveal key similarities and differences among diverse GPCRs. We identify a consensus structural scaffold of GPCRs that is constituted by a network of non-covalent contacts between residues on the transmembrane helices. By systematically analysing structures of the different receptor–ligand complexes, we identify a consensus ‘ligand-binding cradle’ that constitutes the bottom of the ligand-binding pocket within the TM bundle. Furthermore, our comparative study suggests that the third TM helix has a central role as a structural and functional hub. The paper can be found here and the press release by MRC can be found here. Our work was No. 1 in Nature’s top 10 downloaded articles in February 2013, featured in Nature’s GPCR focus section and mentioned in the cover page.

Network based approach to study DNA-DNA contacts published in Nucleic Acids Research

In this paper, we present a general statistical framework that is widely applicable to the analysis of genomic contact maps, irrespective of the data acquisition and normalization processes. Within this framework DNA–DNA contact data are represented as a complex network where DNA segments and contacts between them are denoted as nodes and edges, respectively. We also present a robust method for generating randomized contact networks that explicitly take into account the inherent 3D nature of the genome and serve as realistic null-models for unbiased statistical analyses. Our paper was chosen as a featured article by NAR. The paper by Kai Kruse et al can be found here.

Strategies to control functional and non-functional aggregation published in Cell Reports

Growing evidence suggests that aggregation-prone proteins are both harmful and functional for a cell. How do cellular systems balance the detrimental and beneficial effect of protein aggregation? In this work, we reveal that aggregation-prone proteins are subject to differential transcriptional, translational, and degradation control compared to nonaggregation-prone proteins, which leads to their decreased synthesis, low abundance, and high turnover. Genetic modulators that enhance the aggregation phenotype are enriched in genes that influence expression homeostasis. Moreover, genes encoding aggregation-prone proteins are more likely to be harmful when overexpressed. The trends are evolutionarily conserved and suggest a strategy whereby cellular mechanisms specifically modulate the availability of aggregation-prone proteins to (1) keep concentrations below the critical ones required for aggregation and (2) shift the equilibrium between the monomeric and oligomeric/aggregate form, as explained by Le Chatelier’s principle. This strategy may prevent formation of undesirable aggregates and keep functional assemblies/aggregates under control. The paper can be found here.

Perspective on Intrinsically Disordered Regions published in Science

In this perspective piece, we discuss the notion that disordered regions are largely passive is being actively challenged by the idea that they perform diverse functions. We also discuss how the synergy between structured and disordered regions expands the functional repertoires of proteins. You can read the Perspective here and an accompanying news article here.

Collaborative research with Sarah Teichmann’s group published in Molecular Cell

Through a systematic effort that integrated multiple genome-scale datasets describing various aspects of DNA binding proteins, we show that activators tend to have binding site similarity to nucleosomal histones, resulting in competition for binding to DNA, while repressors show the opposite trend. You can read the paper here and the LMB press release here.

Joint research on chromosome organisation and histone modification during senescence published in Molecular Cell

In this work, we show that nuclear rearrangement of repressive histone marks H3K9me3 and H3K27me3 into nonoverlapping structural layers characterizes senescence-associated heterochromatic foci (SAHF) formation in human fibroblasts. The experiments reveal that high-order heterochromatin formation and epigenetic remodeling of the genome can be discrete events. The paper by Chandra et al. can be read here.

Research on rewiring molecular interactions published in Molecular Cell

Our work on how tissue-specifically spliced segments can rewire protein interactions through disordered segments has been published in Molecular Cell. This work, which has been carried out over the last three years integrates multiple large-scale dataset to arrive at a general principle on how splicing can rewire interactions. The work received coverage in Nature Reviews Genetics and the Gates Trust. The press release on the LMB website can be read here.

Tissue-specific splicing rewires interaction networks

Our review on expression noise in Trends in Genetics

The review on interplay between gene expression stochasticity and network was featured as a cover article in Trends in Genetics. In this work, we discuss and present new ideas on how gene expression noise can be tolerated, buffered or amplified by transcriptional networks. You can read the news item released by the Gates Trust here.