Associative memory in gene regulation networks

The pattern of gene expression in the phenotype of an organism is determined in part by the dynamical attractors of the organism’s gene regulation network. Changes to the connections in this network over evolutionary time alter the adult gene expression pattern and hence the fitness of the organism. However, the evolution of structure in gene expression networks (potentially reflecting past selective environments) and its affordances and limitations with respect to enhancing evolvability is poorly understood in general. In this paper we model the evolution of a gene regulation network in a controlled scenario. We show that selected changes to connections in the regulation network make the currently selected gene expression pattern more robust to environmental variation. Moreover, such changes to connections are necessarily ‘Hebbian’ – ‘genes that fire together wire together’ – i.e. genes whose expression is selected for in the same selective environments become co-regulated. Accordingly, in a manner formally equivalent to well-understood learning behaviour in artificial neural networks, a gene expression network will therefore develop a generalised associative memory of past selected phenotypes. This theoretical framework helps us to better understand the relationship between homeostasis and evolvability (i.e. selection to reduce variability facilitates structured variability), and shows that, in principle, a gene regulation network has the potential to develop ‘recall’ capabilities normally reserved for cognitive systems

Dietary macronutrient composition impacts gene regulation in adipose tissue

Diet is a key lifestyle component that influences metabolic health through several factors, including total energy intake and macronutrient composition. While the impact of caloric intake on gene expression and physiological phenomena in various tissues is well described, the influence of dietary macronutrient composition on these parameters is less well studied. Here, we use the Nutritional Geometry framework to investigate the role of macronutrient composition on metabolic function and gene regulation in adipose tissue. Using ten isocaloric diets that vary systematically in their proportion of energy from fat, protein, and carbohydrates, we find that gene expression and splicing are highly responsive to macronutrient composition, with distinct sets of genes regulated by different macronutrient interactions. Specifically, the expression of many genes associated with Bardet-Biedl syndrome is responsive to dietary fat content. Splicing and expression changes occur in largely separate gene sets, highlighting distinct mechanisms by which dietary composition influences the transcriptome and emphasizing the importance of considering splicing changes to more fully capture the gene regulation response to environmental changes such as diet. Our study provides insight into the gene regulation plasticity of adipose tissue in response to macronutrient composition, beyond the already well-characterized response to caloric intake

Gene regulation and epigenotype in Friedreich's ataxia

Friedreich??????s ataxia (FRDA) is known to be provoked by an abnormal GAA-repeat expansion located in the first intron of the FXN gene. As a result of the GAA expansion, patients exhibit low levels of FXN mRNA, leading to FRDA. Here, via chromatin immunoprecipitation (ChIP), the presence of a RNA pol II transcriptional pausing site at exon 1 of the FXN gene was demonstrated. At this site, FRDA EBVcell lines exhibited elevated levels of the negative elongation factor NELF-E depending on the presence of a GAA repeat expansion compared to controls. This site may represent a rate-limiting step for FXN transcription and consequently provide a means to modify transcription levels in FRDA. Moreover, RNA pol II pausing site binding factors, such as NELF-E, were influenced by Nicotinamide treatment, a HDAC class III inhibitor. Therefore, factors sensitive to chromatin changes may influence the regulation of RNA pol II pausing and also balance otherwise positive chromatin changes. This new finding could explain the relatively minor effects of different drug approaches to up-regulate this gene. Furthermore, CTCF and the histone demethylase LSD1 were also found to be located at the FXN pausing site. Results suggest a function for LSD1 in demethylating H3K4me2 at the pausing site and potentially also in demethylating H3K9me3 in the case of frequently transcribed expanded GAA repeats. Therefore, LSD1 might play a crucial role in preventing heterochromatinisation of a euchromatic gene. Using primary transcript RNA-FISH, a delay in RNA pol II release from the pausing site and furthermore a dramatic loss of RNA pol II elongation in the presence of expanded GAA repeats was seen. The identified and characterised transcriptional pausing site at FXN is likely to play a repressive role and participates in the pathogenesis of FRDA.Imperial Users onl

Keratinocyte differentiation-dependent human papillomavirus gene regulation

Human papillomaviruses (HPVs) cause diseases ranging from benign warts to invasive cancers. HPVs infect epithelial cells and their replication cycle is tightly linked with the differentiation process of the infected keratinocyte. The normal replication cycle involves an early and a late phase. The early phase encompasses viral entry and initial genome replication, stimulation of cell division and inhibition of apoptosis in the infected cell. Late events in the HPV life cycle include viral genome amplification, virion formation, and release into the environment from the surface of the epithelium. The main proteins required at the late stage of infection for viral genome amplification include E1, E2, E4 and E5. The late proteins L1 and L2 are structural proteins that form the viral capsid. Regulation of these late events involves both cellular and viral proteins. The late viral mRNAs are expressed from a specific late promoter but final late mRNA levels in the infected cell are controlled by splicing, polyadenylation, nuclear export and RNA stability. Viral late protein expression is also controlled at the level of translation. This review will discuss current knowledge of how HPV late gene expression is regulated

Mathematical approaches to differentiation and gene regulation

We consider some mathematical issues raised by the modelling of gene networks. The expression of genes is governed by a complex set of regulations, which is often described symbolically by interaction graphs. Once such a graph has been established, there remains the difficult task to decide which dynamical properties of the gene network can be inferred from it, in the absence of precise quantitative data about their regulation. In this paper we discuss a rule proposed by R.Thomas according to which the possibility for the network to have several stationary states implies the existence of a positive circuit in the corresponding interaction graph. We prove that, when properly formulated in rigorous terms, this rule becomes a theorem valid for several different types of formal models of gene networks. This result is already known for models of differential or boolean type. We show here that a stronger version of it holds in the differential setup when the decay of protein concentrations is taken into account. This allows us to verify also the validity of Thomas' rule in the context of piecewise-linear models and the corresponding discrete models. We discuss open problems as well.Comment: To appear in Notes Comptes-Rendus Acad. Sc. Paris, Biologi