ORCID Profile
0000-0001-6428-3175
Current Organisations
Mater Research Institute The University of Queensland
,
Clemson University
,
University of Illinois Urbana-Champaign
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Epigenetics (incl. genome methylation and epigenomics) | Developmental genetics (incl. sex determination) | Genomics and transcriptomics | Genetics |
ANZSRC Socio-Economic Objective (SEO)
Related Links
Publications
Overcoming challenges and dogmas to understand the functions of pseudogenes
Publisher: Springer Science and Business Media LLC
Date: 17-12-2020
DOI: 10.1038/S41576-019-0196-1
Abstract: Pseudogenes are defined as regions of the genome that contain defective copies of genes. They exist across almost all forms of life, and in mammalian genomes are annotated in similar numbers to recognized protein-coding genes. Although often presumed to lack function, growing numbers of pseudogenes are being found to play important biological roles. In consideration of their evolutionary origins and inherent limitations in genome annotation practices, we posit that pseudogenes have been classified on a scientifically unsubstantiated basis. We reflect that a broad misunderstanding of pseudogenes, perpetuated in part by the pejorative inference of the 'pseudogene' label, has led to their frequent dismissal from functional assessment and exclusion from genomic analyses. With the advent of technologies that simplify the study of pseudogenes, we propose that an objective reassessment of these genomic elements will reveal valuable insights into genome function and evolution.
In vivo targeted DamID identifies CHD8 genomic targets in fetal mouse brain
Publisher: Elsevier BV
Date: 11-2021
Cell biology. Insulin finds its niche.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-05-2013
Abstract: Localized insulin signaling allows organ-specific rather than organism-level responses to the environmental conditions.
Integrating deep mutational scanning and low-throughput mutagenesis data to predict the impact of amino acid variants
Publisher: Oxford University Press (OUP)
Date: 28-12-2023
Cell-type-specific profiling of protein-DNA interactions without cell isolation using targeted DamID with next-generation sequencing.
Publisher: Springer Science and Business Media LLC
Date: 04-08-2016
mRNA vaccine quality analysis using RNA sequencing
Publisher: Springer Science and Business Media LLC
Date: 21-09-2023
Zero-field magnetic structure and metamagnetic phase transitions of the cobalt chain compound
Li 2
Publisher: American Physical Society (APS)
Date: 16-10-2023
DamID as a versatile tool for understanding gene regulation
Publisher: The Company of Biologists
Date: 15-03-2019
DOI: 10.1242/DEV.173666
Abstract: The interaction of proteins and RNA with chromatin underlies the regulation of gene expression. The ability to profile easily these interactions is fundamental for understanding chromatin biology in vivo. DNA adenine methyltransferase identification (DamID) profiles genome-wide protein-DNA interactions without antibodies, fixation or protein pull-downs. Recently, DamID has been adapted for applications beyond simple assaying of protein-DNA interactions, such as for studying RNA-chromatin interactions, chromatin accessibility and long-range chromosome interactions. Here, we provide an overview of DamID and introduce improvements to the technology, discuss their applications and compare alternative methodologies.
Methylartist: Tools for Visualising Modified Bases from Nanopore Sequence Data
Publisher: Cold Spring Harbor Laboratory
Date: 23-07-2021
DOI: 10.1101/2021.07.22.453313
Abstract: Methylartist is a consolidated suite of tools for processing, visualising, and analysing nanopore methylation data derived from modified basecalling methods. All detectable methylation types (e.g. 5mCpG, 5hmC, 6mA) are supported, enabling integrated study of base pairs when modified naturally or as part of an experimental protocol. Covalent modification of nucleobases is an important component of genomic regulatory regimes across all domains of life [1–3] and is harnessed by various genomic footprinting assays, including DamID[4], SMAC-seq[5], and NOMe-seq[6]. Nanopore sequencing offers comprehensive assessment of base modifications from arbitrarily long sequence reads through analysis of electrical current profiles, generally through machine learning models trained to discriminate between modified and unmodified bases [7]. An increasing number of computational tools have been developed or enhanced for calling modified bases [8], including nanopolish [7], megalodon [9], and guppy [10], along with an increasing number of available pre-trained models.
Somatic retrotransposition in the developing rhesus macaque brain
Publisher: Cold Spring Harbor Laboratory
Date: 21-06-2022
Abstract: The retrotransposon LINE-1 (L1) is central to the recent evolutionary history of the human genome and continues to drive genetic ersity and germline pathogenesis. However, the spatiotemporal extent and biological significance of somatic L1 activity are poorly defined and are virtually unexplored in other primates. From a single L1 lineage active at the ergence of apes and Old World monkeys, successive L1 subfamilies have emerged in each descendant primate germline. As revealed by case studies, the presently active human L1 subfamily can also mobilize during embryonic and brain development in vivo. It is unknown whether nonhuman primate L1s can similarly generate somatic insertions in the brain. Here we applied approximately 40× single-cell whole-genome sequencing (scWGS), as well as retrotransposon capture sequencing (RC-seq), to 20 hippoc al neurons from two rhesus macaques ( Macaca mulatta ). In one animal, we detected and PCR-validated a somatic L1 insertion that generated target site duplications, carried a short 5′ transduction, and was present in ∼7% of hippoc al neurons but absent from cerebellum and nonbrain tissues. The corresponding donor L1 allele was exceptionally mobile in vitro and was embedded in PRDM4 , a gene expressed throughout development and in neural stem cells. Nanopore long-read methylome and RNA-seq transcriptome analyses indicated young retrotransposon subfamily activation in the early embryo, followed by repression in adult tissues. These data highlight endogenous macaque L1 retrotransposition potential, provide prototypical evidence of L1-mediated somatic mosaicism in a nonhuman primate, and allude to L1 mobility in the brain over the past 30 million years of human evolution.
The Evx1/Evx1as gene locus regulates anterior-posterior patterning during gastrulation.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2016
DOI: 10.1038/SREP26657
Abstract: Thousands of sense-antisense mRNA-lncRNA gene pairs occur in the mammalian genome. While there is usually little doubt about the function of the coding transcript, the function of the lncRNA partner is mostly untested. Here we examine the function of the homeotic Evx1 - Evx1as gene locus. Expression is tightly co-regulated in posterior mesoderm of mouse embryos and in embryoid bodies. Expression of both genes is enhanced by BMP4 and WNT3A, and reduced by Activin. We generated a suite of deletions in the locus by CRISPR-Cas9 editing. We show EVX1 is a critical downstream effector of BMP4 and WNT3A with respect to patterning of posterior mesoderm. The lncRNA, Evx1as arises from alternative promoters and is difficult to fully abrogate by gene editing or siRNA approaches. Nevertheless, we were able to generate a large 2.6 kb deletion encompassing the shared promoter with Evx1 and multiple additional exons of Evx1as. This led to an identical dorsal-ventral patterning defect to that generated by micro-deletion in the DNA-binding domain of EVX1. Thus, Evx1as has no function independent of EVX1, and is therefore unlikely to act in trans . We predict many antisense lncRNAs have no specific trans function, possibly only regulating the linked coding genes in cis .
Targeted DamID reveals differential binding of mammalian pluripotency factors
Publisher: The Company of Biologists
Date: 2018
DOI: 10.1242/DEV.170209
Abstract: The precise control of gene expression by transcription factor networks is critical to organismal development. The predominant approach for mapping transcription factor-chromatin interactions has been chromatin immunoprecipitation (ChIP). However, ChIP requires a large number of homogeneous cells and antisera with high specificity. A second approach, DamID, has the drawback that high levels of Dam methylase are toxic. Here we modify our Targeted DamID approach (TaDa) to enable cell type-specific expression in mammalian systems, generating an inducible system (mammalian TaDa or MaTaDa) to identify protein/DNA interactions in 100 to 1000 times fewer cells than ChIP. We mapped the binding sites of key pluripotency factors, OCT4 and PRDM14, in mouse embryonic stem cells, epiblast-like cells and primordial germ cell-like cells (PGCLCs). PGCLCs are an important system to elucidate primordial germ cell development in mice. We monitored PRDM14 binding during the specification of PGCLCs, identifying direct targets of PRDM14 that are key to understanding its critical role in PGCLC development. We show that MaTaDa is a sensitive and accurate method to assess cell type specific transcription factor binding in limited numbers of cells.
RNA-DamID reveals cell-type-specific binding of roX RNAs at chromatin-entry sites
Publisher: Springer Science and Business Media LLC
Date: 18-12-2018
Processed pseudogenes: A substrate for evolutionary innovation: Retrotransposition contributes to genome evolution by propagating pseudogene sequences with rich regulatory potential throughout the genome.
Publisher: Wiley
Date: 27-09-2021
Abstract: Processed pseudogenes may serve as a genetic reservoir for evolutionary innovation. Here, we argue that through the activity of long interspersed element‐1 retrotransposons, processed pseudogenes disperse coding and noncoding sequences rich with regulatory potential throughout the human genome. While these sequences may appear to be non‐functional, a lack of contemporary function does not prohibit future development of biological activity. Here, we discuss the dynamic evolution of certain processed pseudogenes into coding and noncoding genes and regulatory elements, and their implication in wide‐ranging biological and pathological processes. Also see the video abstract here: youtu.be/iUY_mteVoPI
Reduced chromatin accessibility correlates with resistance to Notch activation
Publisher: Springer Science and Business Media LLC
Date: 25-04-2022
DOI: 10.1038/S41467-022-29834-Z
Abstract: The Notch signalling pathway is a master regulator of cell fate transitions in development and disease. In the brain, Notch promotes neural stem cell (NSC) proliferation, regulates neuronal migration and maturation and can act as an oncogene or tumour suppressor. How NOTCH and its transcription factor RBPJ activate distinct gene regulatory networks in closely related cell types in vivo remains to be determined. Here we use Targeted DamID (TaDa), requiring only thousands of cells, to identify NOTCH and RBPJ binding in NSCs and their progeny in the mouse embryonic cerebral cortex in vivo. We find that NOTCH and RBPJ associate with a broad network of NSC genes. Repression of NSC-specific Notch target genes in intermediate progenitors and neurons correlates with decreased chromatin accessibility, suggesting that chromatin compaction may contribute to restricting NOTCH-mediated transactivation.
High resolution temporal transcriptomics of mouse embryoid body development reveals complex expression dynamics of coding and noncoding loci
Publisher: Springer Science and Business Media LLC
Date: 27-07-2017
DOI: 10.1038/S41598-017-06110-5
Abstract: Cellular responses to stimuli are rapid and continuous and yet the vast majority of investigations of transcriptional responses during developmental transitions typically use long interval time courses limiting the available interpretive power. Moreover, such experiments typically focus on protein-coding transcripts, ignoring the important impact of long noncoding RNAs. We therefore evaluated coding and noncoding expression dynamics at unprecedented temporal resolution (6-hourly) in differentiating mouse embryonic stem cells and report new insight into molecular processes and genome organization. We present a highly resolved differentiation cascade that exhibits coding and noncoding transcriptional alterations, transcription factor network interactions and alternative splicing events, little of which can be resolved by long-interval developmental time-courses. We describe novel short lived and cycling patterns of gene expression and dissect temporally ordered gene expression changes in response to transcription factors. We elucidate patterns in gene co-expression across the genome, describe asynchronous transcription at bidirectional promoters and functionally annotate known and novel regulatory lncRNAs. These findings highlight the complex and dynamic molecular events underlying mammalian differentiation that can only be observed though a temporally resolved time course.
LINE-1 Evasion of Epigenetic Repression in Humans
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.MOLCEL.2019.05.024
Abstract: Epigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells. However, the mechanisms that repress young L1 families and how L1 escapes to cause somatic genome mosaicism in the brain remain unclear. Here we report that a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation in pluripotent and differentiated cells. By analyzing 24 hippoc al neurons with three distinct single-cell genomic approaches, we characterized and validated a somatic L1 insertion bearing a 3' transduction. The source (donor) L1 for this insertion was slightly 5' truncated, lacked the YY1 binding site, and was highly mobile when tested in vitro. Locus-specific bisulfite sequencing revealed that the donor L1 and other young L1s with mutated YY1 binding sites were hypomethylated in embryonic stem cells, during neurodifferentiation, and in liver and brain tissue. These results explain how L1 can evade repression and retrotranspose in the human body.
Long noncoding RNAs and the genetics of cancer.
Publisher: Springer Science and Business Media LLC
Date: 09-05-2013
DOI: 10.1038/BJC.2013.233
Long-read cDNA sequencing identifies functional pseudogenes in the human transcriptome
Publisher: Cold Spring Harbor Laboratory
Date: 30-03-2021
DOI: 10.1101/2021.03.29.437610
Abstract: Pseudogenes are gene copies presumed to mainly be functionless relics of evolution due to acquired deleterious mutations or transcriptional silencing. When transcribed, pseudogenes may encode proteins or enact RNA-intrinsic regulatory mechanisms. However, the extent, characteristics and functional relevance of the human pseudogene transcriptome are unclear. Short-read sequencing platforms have limited power to resolve and accurately quantify pseudogene transcripts owing to the high sequence similarity of pseudogenes and their parent genes. Using deep full-length PacBio cDNA sequencing of normal human tissues and cancer cell lines, we identify here hundreds of novel transcribed pseudogenes. Pseudogene transcripts are expressed in tissue-specific patterns, exhibit complex splicing patterns and contribute to the coding sequences of known genes. We survey pseudogene transcripts encoding intact open reading frames (ORFs), representing potential unannotated protein-coding genes, and demonstrate their efficient translation in cultured cells. To assess the impact of noncoding pseudogenes on the cellular transcriptome, we delete the nucleus-enriched pseudogene PDCL3P4 transcript from HAP1 cells and observe hundreds of perturbed genes. This study highlights pseudogenes as a complex and dynamic component of the transcriptional landscape underpinning human biology and disease.
MaveDB v2: a curated community database with over three million variant effects from multiplexed functional assays
Publisher: Cold Spring Harbor Laboratory
Date: 30-11-2021
DOI: 10.1101/2021.11.29.470445
Abstract: A central problem in genomics is understanding the effect of in idual DNA variants. Multiplexed Assays of Variant Effect (MAVEs) can help address this challenge by measuring all possible single nucleotide variant effects in a gene or regulatory sequence simultaneously. Here we describe MaveDB v2, which has become the database of record for MAVEs. MaveDB now contains a large fraction of published studies, comprising over two hundred datasets and three million variant effect measurements. We created tools and APIs to streamline data submission and access, transforming MaveDB into a hub for the analysis and dissemination of these impactful datasets.
Freedom of expression: cell-type-specific gene profiling
Publisher: Wiley
Date: 29-08-2014
DOI: 10.1002/WDEV.149
Abstract: Cell fate and behavior are results of differential gene regulation, making techniques to profile gene expression in specific cell types highly desirable. Many methods now enable investigation at the DNA, RNA and protein level. This review introduces the most recent and popular techniques, and discusses key issues influencing the choice between these such as ease, cost and applicability of information gained. Interdisciplinary collaborations will no doubt contribute further advances, including not just in single cell type but single-cell expression profiling.
Nanopore Sequencing Enables Comprehensive Transposable Element Epigenomic Profiling
Publisher: Elsevier BV
Date: 12-2020
Mapping RNA–Chromatin Interactions In Vivo with RNA-DamID
Publisher: Springer US
Date: 2020
Pinstripe: a suite of programs for integrating transcriptomic and proteomic datasets identifies novel proteins and improves differentiation of protein-coding and non-coding genes.
Publisher: Oxford University Press (OUP)
Date: 07-10-2012
DOI: 10.1093/BIOINFORMATICS/BTS582
Abstract: Motivation: Comparing transcriptomic data with proteomic data to identify protein-coding sequences is a long-standing challenge in molecular biology, one that is exacerbated by the increasing size of high-throughput datasets. To address this challenge, and thereby to improve the quality of genome annotation and understanding of genome biology, we have developed an integrated suite of programs, called Pinstripe. We demonstrate its application, utility and discovery power using transcriptomic and proteomic data from publicly available datasets. Results: To demonstrate the efficacy of Pinstripe for large-scale analysis, we applied Pinstripe’s reverse peptide mapping pipeline to a transcript library including de novo assembled transcriptomes from the human Illumina Body Atlas (IBA2) and GENCODE v10 gene annotations, and the EBI Proteomics Identifications Database (PRIDE) peptide database. This analysis identified 736 canonical open reading frames (ORFs) supported by three or more PRIDE peptide fragments that are positioned outside any known coding DNA sequence (CDS). Because of the unfiltered nature of the PRIDE database and high probability of false discovery, we further refined this list using independent evidence for translation, including the presence of a Kozak sequence or functional domains, synonymous/non-synonymous substitution ratios and ORF length. Using this integrative approach, we observed evidence of translation from a previously unknown let7e primary transcript, the archetypical lncRNA H19, and a homolog of RD3. Reciprocally, by exclusion of transcripts with mapped peptides or significant ORFs (& codon), we identify 32 187 loci with RNAs longer than 2000 nt that are unlikely to encode proteins. Availability and implementation: Pinstripe (pinstripe.matticklab.com) is freely available as source code or a Mono binary. Pinstripe is written in C# and runs under the Mono framework on Linux or Mac OS X, and both under Mono and .Net under Windows. Contact: m.dinger@garvan.org.au or j.mattick@garvan.org.au Supplementary information: Supplementary data are available at Bioinformatics online.
Microdeletion of 9q22.3: A patient with minimal deletion size associated with a severe phenotype.
Publisher: Wiley
Date: 07-05-2021
DOI: 10.1002/AJMG.A.62224
Abstract: Basal cell nevus syndrome (also known as Gorlin Syndrome MIM109400) is an autosomal dominant disorder characterized by recurrent pathological features such as basal cell carcinomas and odontogenic keratocysts as well as skeletal abnormalities. Most affected in iduals have point mutations or small insertions or deletions within the PTCH1 gene on human chromosome 9, but there are some cases with more extensive deletion of the region, usually including the neighboring FANCC and/or ERCC6L2 genes. We report a 16‐year‐old patient with a deletion of approximately 400,000 bases which removes only PTCH1 and some non‐coding RNA genes but leaves FANCC and ERCC6L2 intact. In spite of the small amount of DNA for which he is haploid, his phenotype is more extreme than many in iduals with longer deletions in the region. This includes early presentation with a large number of basal cell nevi and other skin lesions, multiple jaw keratocysts, and macrosomia. We found that the deletion was in the paternal chromosome, in common with other macrosomia cases. Using public databases, we have examined possible interactions between sequences within and outside the deletion and speculate that a regulatory relationship exists with flanking genes, which is unbalanced by the deletion, resulting in abnormal activation or repression of the target genes and hence the severity of the phenotype.
Nanopore sequencing enables comprehensive transposable element epigenomic profiling
Publisher: Cold Spring Harbor Laboratory
Date: 24-05-2020
DOI: 10.1101/2020.05.24.113068
Abstract: We apply long-read nanopore sequencing and a new tool, TLDR (Transposons from Long Dirty Reads), to directly infer CpG methylation of new and extant human transposable element (TE) insertions in hippoc us, heart, and liver, as well as paired tumour and non-tumour liver. Whole genome TLDR analysis greatly facilitates studies of TE biology as complete insertion sequences and their epigenetic modifications are readily obtainable.
Single-molecule simultaneous profiling of DNA methylation and DNA-protein interactions with Nanopore-DamID
Publisher: Cold Spring Harbor Laboratory
Date: 10-08-2021
DOI: 10.1101/2021.08.09.455753
Abstract: We present Nanopore-DamID, a method to simultaneously detect cytosine methylation and DNA-protein interactions from single molecules, via selective sequencing of adenine-labelled DNA. Assaying LaminB1 and CTCF binding with Nanopore-DamID, we identify escape from LAD-associated repression of hypomethylated promoters amidst generalised hypermethylation of LaminB1-associated regulatory elements. We detect novel CTCF binding sites in highly repetitive regions, and allele-specific CTCF binding to imprinted genes and the active X chromosome. Nanopore-DamID highlights the importance of DNA methylation to transcription factor activity.
Related Organisations
National Institute Of Standards And Technology
Location: United States of America
Mater Research Institute The University Of Queensland
Location: Australia
University Of Illinois Urbana-Champaign
Location: United States of America
University Of Cambridge
Location: United Kingdom of Great Britain and Northern Ireland
Gurdon Institute: University Of Cambridge
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
Deciphering Global And Locus-specific Regulation Of LINE-1 Retrotransposons In Cancer
Start Date: 2019
End Date: 2022
Funder: National Health and Medical Research Council
View Funded ActivityDiscovery Early Career Researcher Award - Grant ID: DE230100036
Start Date: 2023
End Date: 12-2025
Amount: $465,803.00
Funder: Australian Research Council
View Funded Activity