Causes and consequences of stochastic processes in development and disease

Recent developments in genomics indicate that epigenetic alterations may play an important causal role in predisposing normal cells to neoplastic transformation. Professor Teschendorff will begin by presenting data that support an epigenetic stem cell model of oncogenesis, according to which DNA methylation (DNAm) changes that accrue in normal cells as a function of age and other cancer risk factors, lead to differentiation defects and increased aberrant plasticity, promoting cancer development. In the context of two cancers (cervical and breast), he will demonstrate how specific DNAm changes in normal tissue can discriminate those tissues at future risk of neoplastic transformation from those that remain healthy. In the earliest stages these DNAm changes are inherently stochastic across individuals but exhibit selection and convergence upon neoplastic transformation. He will also describe how DNAm changes can be used to measure mitotic-age of tissues, and that DNAm-based mitotic clocks could be used for cancer risk prediction. In the last part of the talk, Professor Teschendorff will describe the group's efforts to quantify cancer risk at the resolution of single-cells via a bottom-up network model that quantifies dedifferentiation from single-cell RNA-Seq data in terms of diffusion entropy. Specifically, he will show how in the context of a multi-stage model of oesophageal cancer development, diffusion entropy identifies the precancerous cells that undergo selection during cancer progression. Mounting evidence points towards underlying epigenetic alterations being better cancer risk markers than genetic mutations or copy-number changes. He will end by discussing the implications of these findings for developing cancer risk prediction strategies.

Professor Andrew Teschendorff, CAS Key Lab of Computational Biology, Shanghai Institute for Nutrition and Health, Chinese Academy of Sciences, China

Professor Andrew Teschendorff, CAS Key Lab of Computational Biology, Shanghai Institute for Nutrition and Health, Chinese Academy of Sciences, China

Andrew Teschendorff studied Mathematical Physics at the University of Edinburgh. In 2000 he obtained his PhD in Theoretical Physics from Cambridge University. From 2003 to 2008 he held Cambridge-MIT and Isaac Newton awards to perform research in Statistical Cancer Genomics at the University of Cambridge. From 2008 to 2013 he held the Heller Research Fellowship at the UCL Cancer Institute in London. In 2013 he moved to Shanghai where he currently is a PI at the CAS Key Lab of Computational Biology, part of the Shanghai Institute for Nutrition and Health. From 2015 to 2019 he held an International Newton Advanced Fellowship from the Royal Society in association with UCL London. His broad research interests include Statistical Cancer Epigenomics, Cancer System-omics and Cancer Risk Prediction. He is an associate editor for Genome Biology, and reviewer and statistical advisor for Nature, NEJM and Science. He holds patents on algorithms for cancer risk prediction and cell-type deconvolution.

Cilia are membrane-encased organelles present on the surface of most cells that rely upon intraflagellar transport (IFT) for their formation and function. Missense mutations in IFT genes cause skeletal, limb, eye and renal disease, and the group modelled several Ift80 mutations in mice. They find that some tissues are more susceptible to disease than others, and they describe incomplete penetrance in the absence of genetic background variation suggesting that stochastic processes determine disease susceptibility. One missense mutation within a splice acceptor affected multiple modes of gene function at the levels of RNA splicing, protein abundance and protein complex formation. This provides a means to investigate different sources of stochastic noise, and to use this biological variation to understand how mutational effects at different biological levels contribute to disease risk. A large proportion of mutations in human monogenic disease are also likely to be multimodal suggesting a generalised approach to investigate stochastic processes that could be applied to many diseases.

Dr Dagan Jenkins, UCL, UK

Dr Dagan Jenkins, UCL, UK

Dr Jenkins has spent 20 years working on the genetics of human birth defects, especially disorders of the skeleton and in particular ciliopathies. He set up his own lab as an MRC New Investigator and is currently Director of a Wellcome Trust-funded Collaborative Award in Science which focuses on missense mutations in intraflagellar transport (IFT) proteins. Using a combination of gene-editing, affinity proteomics and phenomics his laboratory, together with collaborators in London and Germany, focuses on fundamental genetic principles in relation to genetic threshold effects and developmental pleiotropy. His work has suggested an important role for stochastic processes in determining disease severity.

In this talk, Dr Pina will discuss the contributions of epigenetic heterogeneity and transcriptional noise in initiation and maintenance of Acute Myeloid Leukaemia. She will focus on KAT2A, a histone acetyltransferase (HAT) previously shown to regulate transcriptional noise levels in mammalian stem cell systems, and discuss the group's recent observations that Kat2a loss can both promote pre-leukaemia and impede leukaemia maintenance, with similar effects on variability on gene transcription and consequent cell diversification. She will discuss KAT2A roles through specific HAT complex integration, target programmes, and remodelling of gene regulatory networks, and integrate the findings with the transcriptional consequences of other epigenetic complexes previously implicated in regulation of transcriptional noise and progression of leukaemia. Drawing from stem cell and leukaemia models, she will discuss gene-specific responses to transcriptional noise modulation, and suggest potential contextual contributions to functional outcomes and putative value as markers of leukaemia progression and therapeutic response.

Dr Cristina Pina, Brunel University London, UK

Dr Cristina Pina, Brunel University London, UK

Cristina Pina is a Senior Lecturer in Biomedical Sciences at Brunel University London. Her research focuses on the contribution of non-genetic variability, and specifically transcriptional noise, to cell fate decisions and leukaemia evolution. Cristina studied and practised Medicine in Portugal, before deciding to switch careers to research. She did her DPhil in Oxford with Tariq Enver on transcriptional programming of cord blood haematopoietic stem cells. In her first post-doc at UCL, she pioneered the use of single-cell transcriptomics in the haematopoietic system to understand mechanisms of lineage decision. After a short post-doc in Cambridge with Brian Huntly on mouse models of leukaemia, Cristina gained a KKLF Intermediate Fellowship and a Leuka John Goldman Fellowship to launch her independent research. She moved to Brunel in 2019, where she combines research and teaching roles. Cristina is mother to two children.

Chemical reactions serve as basic units for cellular information processing and control. However, reactions in cells are noisy, leading to substantial variability in the molecular constitution of genetically identical cells. How cells deal with such noise has been important question in quantitative biology. In this talk, Dr Zechner will discuss how the mesoscale organisation of molecules into condensates can be used by cells to suppress cellular noise. Using concepts from statistical physics and control theory, he will show that condensates mediate negative feedback, which maintains concentration levels at precise set points in the presence of noise. He will present experimental single-cell data from synthetic and endogenous systems supporting this prediction.

Dr Christoph Zechner, Max Planck Institute of Molecular Cell Biology and Genetics, Germany

Dr Christoph Zechner, Max Planck Institute of Molecular Cell Biology and Genetics, Germany

After finishing his Master’s degree in Telematics at TU Graz in 2010, Zechner relocated to the Automatic Control Lab at ETH Zurich to work on his PhD thesis under the supervision of Heinz Koeppl. After his graduation in 2014, Zechner joined the lab of Mustafa Khammash at the BSSE in Basel as a SystemsX.ch fellow. In early 2017 he started his own independent lab at the MPI-CBG / CSBD focussing on the role of stochasticity in biological systems.

Stochastic mechanisms diversify cell fates during development. How cells randomly choose between two or more fates remains poorly understood. In the Drosophila eye, the random mosaic of two R7 photoreceptor subtypes is determined by expression of the transcription factor Spineless (Ss). The group investigated how cis-regulatory elements and trans factors regulate nascent transcriptional activity and chromatin compaction at the ss gene locus during R7 development. The ss locus is in a compact state in undifferentiated cells. An early enhancer drives transcription in all R7 precursors, and the locus opens. In differentiating cells, transcription ceases and the ss locus stochastically remains open or compacts. In Ss^ON R7s, ss is open and competent for activation by a late enhancer, whereas in Ss^OFF R7s, ss is compact, and repression prevents expression. These results suggest that a temporally dynamic antagonism, in which transcription drives large-scale decompaction and then compaction represses transcription, controls stochastic fate specification.

Associate Professor Robert J Johnston Jr, Johns Hopkins University, USA

Associate Professor Robert J Johnston Jr, Johns Hopkins University, USA

Robert J Johnston Jr is an associate professor in the Department of Biology at Johns Hopkins University. The goal of his research program is to understand the developmental mechanisms that underlie vision. The Johnston lab studies highly divergent fruit fly and human retinal organoid systems to identify fundamental mechanisms that specialize neuronal function. His studies uncovered an antagonistic relationship between noisy transcription and chromatin compaction that produces the random mosaic of photoreceptors in the fruit fly eye. The Johnston lab identified signalling mechanisms that specify subtypes of light-detecting cone photoreceptors and information-transmitting retinal ganglion cells in human retinal organoids.

Gene expression in individual cells can be surprisingly noisy. In unicellular organisms this noise can be functional. For example, it can allow a fraction of the population to survive a sudden environmental stress. The role of gene expression noise in multicellular organisms is less clear. In this talk, Dr Locke will show how new techniques are revealing an unexpected level of variability in gene expression between and within genetically identical plants. He will discuss evidence that transcriptional noise can act as a mechanism for generating functional phenotypic diversity in plants.

Dr James Locke, University of Cambridge, UK

Dr James Locke, University of Cambridge, UK

James graduated from the University of Warwick (2000) in Physics, before completing Maths Part III at Cambridge (2001). James then studied for a joint PhD in Biology and Theoretical Physics at the University of Warwick. He conducted his postdoctoral work in the lab of Professor Michael Elowitz at the California Institute of Technology. He applied single cell time-lapse microscopy, modelling, and synthetic biology techniques to understand how cells amplify small molecule differences (noise) into alternative transcriptional states. 

Since 2012 James has been a group leader at the Sainsbury laboratory at the University of Cambridge. His group is using movies to examine gene expression at the single-cell level in bacteria, cyanobacteria and plants.

 

 

Development from fertilised egg to functioning multi-cellular organism requires precision. Precision can only be achieved through plasticity. Plasticity is conferred in part by stochastic variation, which is inherently present in biological systems. Gene expression levels fluctuate at multiple stages: transcription, alternative splicing, translation, and turnover. Evolving multicellularity and cellular specialisation have exploited the small differences in gene expression to confer distinct functions on selected individual cells. This initial differentiation sets in motion regulatory interactions allowing the non-selected cells to acquire new functions along the spatiotemporal developmental trajectory. Many other components of the differentiation process are stochastic. The dynamic binding of transcriptional regulatory assemblies to DNA exhibit randomness. X-inactivation is normally random, non-random inactivation is generally a sign of mutational perturbation. Correct neural wiring arises through random connections, followed by maintenance only for functional links. This mechanism is well illustrated for the retina. In immune system development both antibody maturation in B cells and the emergence of a balanced population of T-cells begins through stochastic trial and error followed by functional selection. Multiple manifestations of disease arise when the switch from random fluctuation to established pattern selection fails. A wide spectrum of mostly deleterious DNA mutations through stochastic fluctuation in environmental factors: such as levels of radiation or presence of pollutants. The phenotypic outcome of mutations is dependent on variability across genomic functions and the environment. Variable environmental factors also determine which mutations prove advantageous. To ensure population survival, bet-hedging stochastic strategies are often deployed.

Professor Veronica Van Heyningen FRS, University of Edinburgh, UK

Professor Veronica Van Heyningen FRS, University of Edinburgh, UK

"Veronica van Heyningen, formerly Head of the Medical and Developmental Genetics Section, is a Group Leader at the MRC Human Genetics Unit, MRC IGMM at the University of Edinburgh.  The group’s work with human developmental disease brought insight into the mechanisms of cis-regulatory control, revealing the long control regions flanking many developmental regulator genes.  Studies of extra-genic chromosomal rearrangements and non-coding region mutations prompted work, in mouse and zebrafish model systems, on enhancer interactions and transcription factor binding specificity.  Genome-wide target predictions for PAX6 have revealed network complexity and the precision of target-sequence specificity.  Veronica was appointed a CBE for services to science, is an EMBO Member and a Fellow of the Royal Society of Edinburgh, the Academy of Medical Sciences and of the Royal Society."