ORCID Profile
0000-0003-3716-1783
Current Organisations
UNSW Sydney
,
Garvan Institute of Medical Research
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Gene Expression (incl. Microarray and other genome-wide approaches) | Bioinformatics | Genetics | Systems Biology | Cell and Nuclear Division
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-12-2022
Abstract: DNA methylation [5-methylcytosine (5mC)] is a repressive gene-regulatory mark required for vertebrate embryogenesis. Genomic 5mC is tightly regulated through the action of DNA methyltransferases, which deposit 5mC, and ten-eleven translocation (TET) enzymes, which participate in its active removal through the formation of 5-hydroxymethylcytosine (5hmC). TET enzymes are essential for mammalian gastrulation and activation of vertebrate developmental enhancers however, to date, a clear picture of 5hmC function, abundance, and genomic distribution in nonvertebrate lineages is lacking. By using base-resolution 5mC and 5hmC quantification during sea urchin and lancelet embryogenesis, we shed light on the roles of nonvertebrate 5hmC and TET enzymes. We find that these invertebrate deuterostomes use TET enzymes for targeted demethylation of regulatory regions associated with developmental genes and show that the complement of identified 5hmC-regulated genes is conserved to vertebrates. This work demonstrates that active 5mC removal from regulatory regions is a common feature of deuterostome embryogenesis suggestive of an unexpected deep conservation of a major gene-regulatory module.
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.SBI.2014.05.007
Abstract: Intrinsically disordered regions (IDRs) are fundamental units of protein function and regulation. Despite their inability to form a unique stable tertiary structure in isolation, many IDRs adopt a defined conformation upon binding and achieve their function through their interactions with other biomolecules. However, this requirement for IDR functionality seems to be at odds with the high entropic cost they must incur upon binding an interaction partner. How is this seeming paradox resolved? While increasing the enthalpy of binding is one approach to compensate for this entropic cost, growing evidence suggests that inherent features of IDRs, for instance repeating linear motifs, minimise the entropic cost of binding. Moreover, this control of entropic cost can be carefully modulated by a range of regulatory mechanisms, such as alternative splicing and post-translational modifications, which enable allosteric communication and rheostat-like tuning of IDR function. In that sense, the high entropic cost of IDR binding can be advantageous by providing tunability to protein function. In addition to biological regulatory mechanisms, modulation of entropy can also be controlled by environmental factors, such as changes in temperature, redox-potential and pH. These principles are extensively exploited by a number of organisms, including pathogens. They can also be utilised in bioengineering, synthetic biology and in pharmaceutical applications such as increasing bioavailability of protein therapeutics.
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.BIOPSYCH.2022.04.021
Abstract: The higher-order cognitive functions observed in primates correlate with the evolutionary enhancement of cortical volume and folding, which in turn are driven by the primate-specific expansion of cellular ersity in the developing cortex. Underlying these changes is the ersification of molecular features including the creation of human and/or primate-specific genes, the activation of specific molecular pathways, and the interplay of erse layers of gene regulation. We review and discuss evidence for connections between Alu elements and primate brain evolution, the evolutionary milestones of which are known to coincide along primate lineages. Alus are repetitive elements that contribute extensively to the acquisition of novel genes and the expansion of erse gene regulatory layers, including enhancers, alternative splicing, RNA editing, and microRNA pathways. By reviewing the impact of Alus on molecular features linked to cortical expansions or gyrification or implications in cognitive deficits, we suggest that future research focusing on the role of Alu-derived molecular events in the context of brain development may greatly advance our understanding of higher-order cognitive functions and neurologic disorders.
Publisher: Springer Science and Business Media LLC
Date: 17-07-2019
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.GIM.2021.09.001
Abstract: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). A total of 74 families with erse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with s les from ≥2 affected in iduals or heterozygotes and 10 cases with ≥2 biospecimens. PCR licons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long licons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.
Publisher: Oxford University Press (OUP)
Date: 24-05-2012
DOI: 10.1093/NAR/GKS442
Publisher: Elsevier BV
Date: 08-2016
Publisher: eLife Sciences Publications, Ltd
Date: 20-09-2021
DOI: 10.7554/ELIFE.69148
Abstract: Many primate genes produce circular RNAs (circRNAs). However, the extent of circRNA conservation between closely related species remains unclear. By comparing tissue-specific transcriptomes across over 70 million years of primate evolution, we identify that within 3 million years circRNA expression profiles erged such that they are more related to species identity than organ type. However, our analysis also revealed a subset of circRNAs with conserved neural expression across tens of millions of years of evolution. By comparing to species-specific circRNAs, we identified that the downstream intron of the conserved circRNAs display a dramatic lengthening during evolution due to the insertion of novel retrotransposons. Our work provides comparative analyses of the mechanisms promoting circRNAs to generate increased transcriptomic complexity in primates.
Publisher: Elsevier BV
Date: 12-2014
Publisher: Springer Science and Business Media LLC
Date: 24-08-2014
DOI: 10.1038/NSMB.2876
Publisher: American Chemical Society (ACS)
Date: 29-04-2014
DOI: 10.1021/CR400525M
Publisher: Oxford University Press (OUP)
Date: 25-05-2012
DOI: 10.1093/NAR/GKS444
Publisher: Springer Science and Business Media LLC
Date: 23-03-2023
DOI: 10.1038/S41587-023-01714-X
Abstract: An average shotgun proteomics experiment detects approximately 10,000 human proteins from a single s le. However, in idual proteins are typically identified by peptide sequences representing a small fraction of their total amino acids. Hence, an average shotgun experiment fails to distinguish different protein variants and isoforms. Deeper proteome sequencing is therefore required for the global discovery of protein isoforms. Using six different human cell lines, six proteases, deep fractionation and three tandem mass spectrometry fragmentation methods, we identify a million unique peptides from 17,717 protein groups, with a median sequence coverage of approximately 80%. Direct comparison with RNA expression data provides evidence for the translation of most nonsynonymous variants. We have also hypothesized that undetected variants likely arise from mutation-induced protein instability. We further observe comparable detection rates for exon–exon junction peptides representing constitutive and alternative splicing events. Our dataset represents a resource for proteoform discovery and provides direct evidence that most frame-preserving alternatively spliced isoforms are translated.
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.MOLCEL.2022.06.036
Abstract: Alternative splicing (AS) is a critical regulatory layer yet, factors controlling functionally coordinated splicing programs during developmental transitions are poorly understood. Here, we employ a screening strategy to identify factors controlling dynamic splicing events important for mammalian neurogenesis. Among previously unknown regulators, Rbm38 acts widely to negatively control neural AS, in part through interactions mediated by the established repressor of splicing, Ptbp1. Puf60, a ubiquitous factor, is surprisingly found to promote neural splicing patterns. This activity requires a conserved, neural-differential exon that remodels Puf60 co-factor interactions. Ablation of this exon rewires distinct AS networks in embryonic stem cells and at different stages of mouse neurogenesis. Single-cell transcriptome analyses further reveal distinct roles for Rbm38 and Puf60 isoforms in establishing neuronal identity. Our results describe important roles for previously unknown regulators of neurogenesis and establish how an alternative exon in a widely expressed splicing factor orchestrates temporal control over cell differentiation.
Publisher: Springer Science and Business Media LLC
Date: 05-04-2023
DOI: 10.1038/S41398-023-02391-9
Abstract: Autism spectrum disorder (ASD) includes a set of highly heritable neurodevelopmental syndromes characterized by social and communication impairment, repetitive behaviour, and intellectual disability. Although mutations in multiple genes have been associated to ASD, most patients lack detectable genetic alterations. For this reason, environmental factors are commonly thought to also contribute to ASD aetiology. Transcriptome analyses have revealed that autistic brains possess distinct gene expression signatures, whose elucidation can provide insights about the mechanisms underlying the effects of ASD-causing genetic and environmental factors. Herein, we have identified a coordinated and temporally regulated programme of gene expression in the post-natal development of cerebellum, a brain area whose defects are strongly associated with ASD. Notably, this cerebellar developmental programme is significantly enriched in ASD-linked genes. Clustering analyses highlighted six different patterns of gene expression modulated during cerebellar development, with most of them being enriched in functional processes that are frequently dysregulated in ASD. By using the valproic acid mouse model of ASD, we found that ASD-linked genes are dysregulated in the developing cerebellum of ASD-like mice, a defect that correlates with impaired social behaviour and altered cerebellar cortical morphology. Moreover, changes in transcript levels were reflected in aberrant protein expression, indicating the functional relevance of these alterations. Thus, our work uncovers a complex ASD-related transcriptional programme regulated during cerebellar development and highlight genes whose expression is dysregulated in this brain area of an ASD mouse model.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-12-2013
Publisher: eLife Sciences Publications, Ltd
Date: 30-08-2021
Publisher: Springer Science and Business Media LLC
Date: 02-11-2018
DOI: 10.1038/S41576-018-0066-2
Abstract: Heredity has a major role in autism spectrum disorder (ASD), yet underlying causal genetic variants have been defined only in a fairly small subset of cases. The enormous genetic heterogeneity associated with ASD emphasizes the importance of identifying convergent pathways and molecular mechanisms that are responsible for this disorder. We review how recent transcriptomic analyses have transformed our understanding of pathway convergence in ASD. In particular, deep RNA sequencing coupled with downstream investigations has revealed that a substantial fraction of autistic brains possess distinct transcriptomic signatures. These signatures are in part a consequence of altered neuronal activity and have a particular impact on pre-mRNA alternative splicing patterns.
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C1MB05231D
Abstract: Traditionally, protein-protein interactions were thought to be mediated by large, structured domains. However, it has become clear that the interactome comprises a wide range of binding interfaces with varying degrees of flexibility, ranging from rigid globular domains to disordered regions that natively lack structure. Enrichment for disorder in highly connected hub proteins and its correlation with organism complexity hint at the functional importance of disordered regions. Nevertheless, they have not yet been extensively characterised. Shifting the attention from globular domains to disordered regions of the proteome might bring us closer to elucidating the dense and complex connectivity of the interactome. An important class of disordered interfaces are the compact mono-partite, short linear motifs (SLiMs, or eukaryotic linear motifs (ELMs)). They are evolutionarily plastic and interact with relatively low affinity due to the limited number of residues that make direct contact with the binding partner. These features confer to SLiMs the ability to evolve convergently and mediate transient interactions, which is imperative to network evolution and to maintain robust cell signalling, respectively. The ability to discriminate biologically relevant SLiMs by means of different attributes will improve our understanding of the complexity of the interactome and aid development of bioinformatics tools for motif discovery. In this paper, the curated instances currently available in the Eukaryotic Linear Motif (ELM) database are analysed to provide a clear overview of the defining attributes of SLiMs. These analyses suggest that functional SLiMs have higher levels of conservation than their surrounding residues, frequently evolve convergently, preferentially occur in disordered regions and often form a secondary structure when bound to their interaction partner. These results advocate searching for small groupings of residues in disordered regions with higher relative conservation and a propensity to form the secondary structure. Finally, the most interesting conclusions are examined in regard to their functional consequences.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2022
DOI: 10.1038/S41586-022-05054-9
Abstract: The notion that mobile units of nucleic acid known as transposable elements can operate as genomic controlling elements was put forward over six decades ago
Publisher: eLife Sciences Publications, Ltd
Date: 25-03-2016
DOI: 10.7554/ELIFE.10288
Abstract: Progression through the mitotic cell cycle requires periodic regulation of gene function at the levels of transcription, translation, protein-protein interactions, post-translational modification and degradation. However, the role of alternative splicing (AS) in the temporal control of cell cycle is not well understood. By sequencing the human transcriptome through two continuous cell cycles, we identify ~1300 genes with cell cycle-dependent AS changes. These genes are significantly enriched in functions linked to cell cycle control, yet they do not significantly overlap genes subject to periodic changes in steady-state transcript levels. Many of the periodically spliced genes are controlled by the SR protein kinase CLK1, whose level undergoes cell cycle-dependent fluctuations via an auto-inhibitory circuit. Disruption of CLK1 causes pleiotropic cell cycle defects and loss of proliferation, whereas CLK1 over-expression is associated with various cancers. These results thus reveal a large program of CLK1-regulated periodic AS intimately associated with cell cycle control.
Publisher: Wiley
Date: 15-05-2015
DOI: 10.1002/PRO.2674
Publisher: Oxford University Press (OUP)
Date: 10-02-2012
DOI: 10.1093/BIOINFORMATICS/BTS072
Abstract: Motivation: Eukaryotic proteins are highly modular, containing multiple interaction interfaces that mediate binding to a network of regulators and effectors. Recent advances in high-throughput proteomics have rapidly expanded the number of known protein–protein interactions (PPIs) however, the molecular basis for the majority of these interactions remains to be elucidated. There has been a growing appreciation of the importance of a subset of these PPIs, namely those mediated by short linear motifs (SLiMs), particularly the canonical and ubiquitous SH2, SH3 and PDZ domain-binding motifs. However, these motif classes represent only a small fraction of known SLiMs and outside these ex les little effort has been made, either bioinformatically or experimentally, to discover the full complement of motif instances. Results: In this article, interaction data are analysed to identify and characterize an important subset of PPIs, those involving SLiMs binding to globular domains. To do this, we introduce iELM, a method to identify interactions mediated by SLiMs and add molecular details of the interaction interfaces to both interacting proteins. The method identifies SLiM-mediated interfaces from PPI data by searching for known SLiM–domain pairs. This approach was applied to the human interactome to identify a set of high-confidence putative SLiM-mediated PPIs. Availability: iELM is freely available at elmint.embl.de Contact: toby.gibson@embl.de Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Wiley
Date: 22-07-2008
DOI: 10.1002/HBM.20615
Publisher: Proceedings of the National Academy of Sciences
Date: 03-09-2013
Abstract: In higher organisms, most genes consist of several disconnected regions (exons), which are combined in various ways to produce several different gene transcripts from the same gene. Such alternative exon usage is thought to contribute to the ability of organisms to generate different cell types and tissues from a single genome. However, recent evidence has also suggested that much alternative exon usage might be noise with no particular function. We reconcile these two views by comparing how exons are used in different tissues and for which exons these usage patterns across tissues change or stay similar (are “conserved”) in several primate species. The latter case is an indication that the pattern is of functional importance, and our analysis quantifies how widespread such cases are.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2021
DOI: 10.1038/S41467-020-20483-8
Abstract: Previous transcriptomic profiling studies have typically focused on separately analyzing mRNA expression, alternative splicing and alternative polyadenylation differences between cell and tissue types. However, the relative contribution of these three transcriptomic regulatory layers to cell type specification is poorly understood. This question is particularly relevant to neurons, given their extensive heterogeneity associated with brain location, morphology and function. In the present study, we generated profiles for the three regulatory layers from developmentally and regionally distinct subpopulations of neurons from the mouse hippoc us and broader nervous system. Multi-omics factor analyses revealed differing contributions of each transcriptomic layer in the discrimination of neurons based on their stage of development, region, and function. Importantly, profiles of differential alternative splicing and polyadenylation better discriminated specific neuronal subtype populations than gene expression patterns. These results provide evidence for differential relative contributions of coordinated gene regulatory layers in the specification of neuronal subtypes.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.MOLCEL.2017.01.011
Abstract: Networks of coordinated alternative splicing (AS) events play critical roles in development and disease. However, a comprehensive knowledge of the factors that regulate these networks is lacking. We describe a high-throughput system for systematically linking trans-acting factors to endogenous RNA regulatory events. Using this system, we identify hundreds of factors associated with erse regulatory layers that positively or negatively control AS events linked to cell fate. Remarkably, more than one-third of the regulators are transcription factors. Further analyses of the zinc finger protein Zfp871 and BTB/POZ domain transcription factor Nacc1, which regulate neural and stem cell AS programs, respectively, reveal roles in controlling the expression of specific splicing regulators. Surprisingly, these proteins also appear to regulate target AS programs via binding RNA. Our results thus uncover a large "missing cache" of splicing regulators among annotated transcription factors, some of which dually regulate AS through direct and indirect mechanisms.
Publisher: Springer Science and Business Media LLC
Date: 07-11-2016
DOI: 10.1038/NSMB.3317
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-04-2013
DOI: 10.1126/SCISIGNAL.2003345
Abstract: A resource centered on short linear motifs provides a repository and exploratory tool for conditional protein interactions.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.MOLCEL.2021.12.010
Abstract: The nucleus is highly compartmentalized through the formation of distinct classes of membraneless domains. However, the composition and function of many of these structures are not well understood. Using APEX2-mediated proximity labeling and RNA sequencing, we surveyed human transcripts associated with nuclear speckles, several additional domains, and the lamina. Remarkably, speckles and lamina are associated with distinct classes of retained introns enriched in genes that function in RNA processing, translation, and the cell cycle, among other processes. In contrast to the lamina-proximal introns, retained introns associated with speckles are relatively short, GC-rich, and enriched for functional sites of RNA-binding proteins that are concentrated in these domains. They are also highly differentially regulated across erse cellular contexts, including the cell cycle. Thus, our study provides a resource of nuclear domain-associated transcripts and further reveals speckles and lamina as hubs of distinct populations of retained introns linked to gene regulation and cell cycle progression.
Publisher: Cold Spring Harbor Laboratory
Date: 03-07-2017
DOI: 10.1101/158519
Abstract: Alternative splicing (AS) is a widespread process underlying the generation of transcriptomic and proteomic ersity in metazoans. Major challenges in comprehensively detecting and quantifying patterns of AS are that RNA-seq datasets are expanding near exponentially, while existing analysis tools are computationally inefficient and ineffective at handling complex splicing patterns. Here, we describe Whippet , a method that rapidly, and with minimal hardware requirements, models and quantifies splicing events of any complexity without significant loss of accuracy. Using an entropic measure of splicing complexity, Whippet reveals that approximately 33% of human protein coding genes contain complex AS events that result in substantial expression of multiple splice isoforms. These events frequently affect tandem arrays of folded protein domains. Remarkably, high-entropy AS events are more prevalent in tumour relative to matched normal tissues, and these differences correlate with increased expression of proto-oncogenic splicing factors. Whippet thus affords the rapid and accurate analysis of AS events of any complexity, and as such will facilitate biomedical research.
Publisher: Elsevier BV
Date: 03-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4MB00290C
Abstract: Mutations in short linear motifs impair the functions of intrinsically disordered proteins in cellular signaling/regulation and contribute substantially to human diseases.
Publisher: American Chemical Society (ACS)
Date: 13-06-2014
DOI: 10.1021/CR400585Q
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.CELL.2017.06.037
Abstract: Alternative splicing (AS) patterns have erged rapidly during vertebrate evolution, yet the functions of most species- and lineage-specific splicing events are not known. We observe that mammalian-specific AS events are enriched in transcript sequences encoding intrinsically disordered regions (IDRs) of proteins, in particular those containing glycine/tyrosine repeats that mediate formation of higher-order protein assemblies implicated in gene regulation and human disease. These evolutionary changes impact nearly all members of the hnRNP A and D families of RNA binding proteins. Regulation of these events requires formation of unusual, long-range mammalian-specific RNA duplexes. Differential inclusion of the alternative exons controls the formation of tyrosine-dependent multivalent hnRNP assemblies that, in turn, function to globally regulate splicing. Together, our results demonstrate that AS control of IDR-mediated interactions between hnRNPs represents an important and recurring mechanism underlying splicing regulation. Furthermore, this mechanism has expanded the regulatory capacity of mammalian cells.
Publisher: Cold Spring Harbor Laboratory
Date: 05-2021
DOI: 10.1101/2021.05.01.442284
Abstract: Many primate genes produce non-coding circular RNAs (circRNAs). However, the extent of circRNA conservation between closely related species remains unclear. By comparing tissue-specific transcriptomes across over 70 million years of primate evolution, we identify that within 3 million years circRNA expression profiles erged such that they are more related to species identity than organ type. However, our analysis also revealed a subset of circRNAs with conserved neural expression across tens of millions of years of evolution. These circRNAs are defined by an extended downstream intron that has shown dramatic lengthening during evolution due to the insertion of novel retrotransposons. Our work provides comparative analyses of the mechanisms promoting circRNAs to generate increased transcriptomic complexity in primates.
Publisher: Springer Science and Business Media LLC
Date: 08-04-2020
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.MOLCEL.2018.08.018
Abstract: Alternative splicing (AS) is a widespread process underlying the generation of transcriptomic and proteomic ersity and is frequently misregulated in human disease. Accordingly, an important goal of biomedical research is the development of tools capable of comprehensively, accurately, and efficiently profiling AS. Here, we describe Whippet, an easy-to-use RNA-seq analysis method that rapidly-with hardware requirements compatible with a laptop-models and quantifies AS events of any complexity without loss of accuracy. Using an entropic measure of splicing complexity, Whippet reveals that one-third of human protein coding genes produce transcripts with complex AS events involving co-expression of two or more principal splice isoforms. We observe that high-entropy AS events are more prevalent in tumor relative to matched normal tissues and correlate with increased expression of proto-oncogenic splicing factors. Whippet thus affords the rapid and accurate analysis of AS events of any complexity, and as such will facilitate future biomedical research.
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.TIBS.2012.05.001
Abstract: Pretranslational modification by alternative splicing, alternative promoter usage and RNA editing enables the production of multiple protein isoforms from a single gene. A large quantity of data now supports the notion that short linear motifs (SLiMs), which are protein interaction modules enriched within intrinsically disordered regions, are key for the functional ersification of these isoforms. The inclusion or removal of these SLiMs can switch the subcellular localisation of an isoform, promote cooperative associations, refine the affinity of an interaction, coordinate phase transitions within the cell, and even create isoforms of opposing function. This article discusses the novel functionality enabled by the addition or removal of SLiM-containing exons by pretranslational modifications, such as alternative splicing and alternative promoter usage, and how these alterations enable the creation and modulation of complex regulatory and signalling pathways.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.MOLCEL.2020.01.006
Abstract: Microexons represent the most highly conserved class of alternative splicing, yet their functions are poorly understood. Here, we focus on closely related neuronal microexons overlapping prion-like domains in the translation initiation factors, eIF4G1 and eIF4G3, the splicing of which is activity dependent and frequently disrupted in autism. CRISPR-Cas9 deletion of these microexons selectively upregulates synaptic proteins that control neuronal activity and plasticity and further triggers a gene expression program mirroring that of activated neurons. Mice lacking the Eif4g1 microexon display social behavior, learning, and memory deficits, accompanied by altered hippoc al synaptic plasticity. We provide evidence that the eIF4G microexons function as a translational brake by causing ribosome stalling, through their propensity to promote the coalescence of cytoplasmic granule components associated with translation repression, including the fragile X mental retardation protein FMRP. The results thus reveal an autism-disrupted mechanism by which alternative splicing specializes neuronal translation to control higher order cognitive functioning.
Location: United Kingdom of Great Britain and Northern Ireland
Location: Canada
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 06-2022
End Date: 06-2023
Amount: $925,739.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2020
End Date: 06-2024
Amount: $470,000.00
Funder: Australian Research Council
View Funded Activity