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Denis Thieffry

Publications and source records attributed to Denis Thieffry.

3 recordsLinked to original sources

RSAT matrix-clustering: dynamic exploration and redundancy reduction of transcription factor binding motif collections

Transcription Factor (TF) databases contain multitudes of motifs from various sources, from which non-redundant collections are derived by manual curation. The advent of high-throughput methods stimulated the production of novel collections with increasing numbers of motifs. Meta-databases, built by merging these collections, contain redundant versions, because available tools are not suited to automatically identify and explore biologically relevant clusters among thousands of motifs. Motif discovery from genome-scale data sets (e.g. ChIP-seq peaks) also produces redundant motifs, hampering the interpretation of results. We present matrix-clustering, a versatile tool that clusters similar TFBMs into multiple trees, and automatically creates non-redundant collections of motifs. A feature unique to matrix-clustering is its dynamic visualisation of aligned TFBMs, and its capability to simultaneously treat multiple collections from various sources. We demonstrate that matrix-clustering considerably simplifies the interpretation of combined results from multiple motif discovery tools and highlights biologically relevant variations of similar motifs. By clustering 24 entire databases (>7,500 motifs), we show that matrix-clustering correctly groups motifs belonging to the same TF families, and can drastically reduce motif redundancy. matrix-clustering is integrated within the RSAT suite (http://rsat.eu/), accessible through a user-friendly web interface or command-line for its integration in pipelines.

Bioinformatics

Model checking to assess T-helper cell plasticity

Computational modeling constitutes a crucial step towards the functional understanding of complex cellular networks. In particular, logical modeling has proven suitable for the dynamical analysis of large signaling and transcriptional regulatory networks. In this context, signaling input components are generally meant to convey external stimuli, or environmental cues. In response to such external signals, cells acquire specific gene expression patterns modeled in terms of attractors (e.g. stable states). The capacity for cells to alter or reprogram their differentiated states upon changes in environmental conditions is referred to as cell plasticity.\n\nIn this article, we present a multivalued logical framework along with computational methods recently developed to efficiently analyze large models. We mainly focus on a symbolic model checking approach to investigate switches between attractors subsequent to changes of input conditions.\n\nAs a case study, we consider the cellular network regulating the differentiation of T-helper cells, which orchestrate many physiological and pathological immune responses. To account for novel cellular subtypes, we present an extended version of a published model of T-helper cell differentiation. We then use symbolic model checking to analyze reachability properties between T-helper subtypes upon changes of environmental cues. This allows for the construction of a synthetic view of T-helper cell plasticity in terms of a graph connecting subtypes with arcs labeled by input conditions. Finally, we explore novel strategies enabling specific T-helper cell polarizing or reprograming events.

Systems Biology

Cooperative development of logical modelling standards and tools with CoLoMoTo

The identification of large regulatory and signalling networks involved in the control of crucial cellular processes calls for proper modelling approaches. Indeed, models can help elucidate properties of these networks, understand their behaviour, and provide (testable) predictions by performing in silico experiments. In this context, qualitative, logical frameworks have emerged as relevant approaches as demonstrated by a growing number of published models, along with new methodologies and software tools. This productive activity now requires a concerted effort to ensure model reusability and interoperability between tools. Here, we outline the logical modelling framework and present the most important achievements of the Consortium for Logical Models and Tools, along with future objectives. This open community welcomes contributions from all researchers interested in logical modelling or in related mathematical and computational developments.

Systems Biology