bioRxiv Science⌕ Search

Biology subjects

Ang, Y.

Publications and source records attributed to Ang, Y..

9 recordsLinked to original sources
bioRxiv2024

The metaplastic precursor state to oesophageal adenocarcinoma represents reversion to a transient epithelial cell state in the developing oesophagus

In Barretts oesophagus (BO), the precursor of oesophageal adenocarcinoma, the adult stratified squamous epithelium is replaced by a simple columnar phenotype. This has been considered metaplasia; the inappropriate conversion from one adult cell-type to another. In fact, BO could be a reversal of mammalian embryogenesis when the early foregut is first lined by simple columnar epithelium. Exploring this hypothesis has been hampered by inadequate molecular details of human oesophageal development. Here, we adopted single cell transcriptomic and epigenomic approaches to discover and decode the cell types that constitute the initial primitive columnar, transitory and subsequently stratified lower oesophageal epithelium. Each stage is comprised of several previously undefined epithelial sub-populations. HNF4A, a major driver of the BO phenotype, is a prominent transcriptional regulator in the early foregut columnar cells, but not in the later ciliated or stratified cells, and is central to gene regulatory programmes known to be reactivated in BO. Moreover, GWAS susceptibility SNPs for BO mapped to putative regulatory regions in fetal epithelial cells, which are inaccessible in the corresponding adult epithelial cells. Collectively, these data argue that the path to BO involves reactivation of pathways that define primitive fetal epithelial cell states.

developmental biology↗
bioRxiv2023

An integrative taxonomic treatment of the Mycetophilidae (Diptera: Bibionomorpha) from Singapore reveals 115 new species on 730km2

Abstract"Open ended" or "dark taxa" are species-rich clades that are so abundant and diverse that conventional taxonomic methods tend to struggle with the onslaught of specimens and species. New approaches based on presorting specimens to putative species with low-cost DNA barcodes may make tackling these taxa manageable. However, this will still require limiting the geographic scope of taxonomic revisions, given that most countries and biogeographic regions will have too many specimens and species for comprehensive coverage. We demonstrate the power of this approach by carrying out a revision of the Mycetophilidae fungus gnats (Diptera) of Singapore. The material revised here was obtained from 496 samples collected with 71 Malaise traps placed at 107 sites in different habitats in Singapore: mangroves, swamp forests, freshwater swamps, primary rainforests, and different types of secondary forests (old, maturing, young, urban). Based on molecular and morphological data for 1,454 specimens, we delimit 120 species of 23 genera. Of these, only five were species previously described. The remaining 115 species are new to science and described here. We name, however, only 98 of these species since 14 species are currently only known from females and we cannot prepare a fully satisfying morphological diagnosis (Manota spp. A-G and Neoempheria spp. A-G), and three species lack molecular data (Epicypta sp. A, Epicypta sp. B, and Neoempheria sp. H). To assess congruence between species delimited with DNA barcodes (3% clusters) and morphology, we determined a match ratio and found it to be overall high (95%) with even higher match ratios (99%) observed for MOTUs clustered at 5% with Objective Clustering and MOTUs obtained with ABGD set to (P=0.060). Overall, the ratio of undescribed to described is an astonishing 20:1. Only revising the Singapore fauna increases the number of described species of Oriental Mycetophilidae by about 25%, highlighting the size of the taxonomic impediment for fungus gnats. Most of the Singapore Mycetophilidae diversity belongs to three genera--Neoempheria Osten-Sacken (31 species), Epicypta Winnertz (29 species) and Manota Williston (14 species), but we also describe a new genus-- Integricypta, gen. n., which is the putative sistergroup of Aspidionia Colless--belonging to the Mycetophilinae Mycetophilini based on three species. The species sequenced, illustrated, and named are: Leptomorphus rafflesi, sp. n.; Monoclona simhapura, sp. n.; Azana demeijeri, sp. n.; Azana leekongchiani, sp. n. (Sciophilinae); Tetragoneura crawfurdi, sp. n.; Tetragoneura chola, sp. n.; Tetragoneura dayuan, sp. n.; Tetragoneura farquhari, sp. n.; Ectrepesthoneura johor, sp. n. (Tetragoneurinae); Mohelia zubirsaidi, sp. n.; Allactoneura tumasik, sp. n.; Allactoneura limbosengi, sp. n.; Manota banzu, sp. n.; Manota tantocksengi, sp. n.; Manota bukittimah, sp. n.; Manota chiamassie, sp. n.; Manota danmaxi, sp. n.; Manota mahuan, sp. n.; Manota temenggong, sp. n.; Clastobasis sritribuana, sp. n.; Clastobasis bugis, sp. n.; Clastobasis oranglaut, sp. n. (Leiinae); Parempheriella mait, sp. n.; Parempheriella longyamen, sp. n.; Parempheriella peranakan, sp. n.; Mycomya sachmatich, sp. n.; Neoempheria merlio, sp. n.; Neoempheria sabana, sp. n.; Neoempheria sangabo, sp. n.; Neoempheria shicheng, sp. n.; Neoempheria ujong, sp. n.; Neoempheria subaraji, sp. n.; Neoempheria kokoiyeeae, sp. n.; Neoempheria mandai, sp. n.; Neoempheria malacca, sp. n.; Neoempheria sinkapho, sp. n.; Neoempheria singapura, sp. n.; Neoempheria xinjiapo, sp. n.; Neoempheria puluochung, sp. n.; Neoempheria merdeka, sp. n.; Neoempheria neesoon, sp. n.; Neoempheria pulau, sp. n.; Neoempheria cinkappur, sp. n.; Neoempheria temasek, sp. n.; Neoempheria polunini, sp. n.; Neoempheria fajar, sp. n.; Neoempheria riatanae, sp. n. (Mycomyinae); Brachycampta glorialimae, sp. n.; Brachycampta murphyi, sp. n.; Brachycampta limtzepengi, sp. n.; Rymosia teopohlengi, sp. n.; Exechia tanswiehiani, sp. n.; Exechia alinewongae, sp. n.; Mycetophila chngseoktinae, sp. n.; Mycetophila georgettechenae, sp. n.; Mycetophila aishae, sp. n.; Platyprosthiogyne phanwaithongae, sp. n.; Platyprosthiogyne gohsookhimae, sp. n.; Platyprosthiogyne rahimahae, sp. n.; Platyprosthiogyne lynetteseahae, sp. n.; Platyprosthiogyne neilaae, sp. n.; Platyprosthiogyne snehalethaae, sp. n.; Platurocypta adeleneweeae, sp. n.; Platurocypta tanhoweliangi, sp. n.; Epicypta constancesingamae, sp. n.; Epicypta jennylauae, sp. n.; Epicypta limchiumeiae, sp. n.; Epicypta janetyeeae, sp. n.; Epicypta kohkhenglianae, sp. n.; Epicypta daintoni, sp. n.; Epicypta holltumi, sp.n.; Epicypta ridleyi, sp. n.; Epicypta chezaharaae, sp. n.; Epicypta tanjiakkimi, sp. n.; Epicypta gehminae, sp. n.; Epicypta jackieyingae, sp. n.; Epicypta khatijunae, sp. n.; Epicypta purchoni, sp. n.; Epicypta foomaoshengi, sp. n.; Epicypta ganengsengi, sp. n.; Epicypta nanyangu, sp. n.; Epicypta nus, sp. n.; Epicypta peterngi, sp. n.; Epicypta maggielimae, sp. n.; Epicypta yupeigaoae, sp. n.; Epicypta annwee, sp. n.; Epicypta wallacei, sp. n.; Epicypta lamtoongjini, sp. n.; Epicypta catherinelimae, sp. n.; Epicypta grootaerti, sp. n.; Epicypta joaquimae, sp. n.; Aspidionia cheesweeleeae, sp. n.; Aspidionia janetjesudasonae, sp. n.; Aspidionia fatimahae, sp. n.; Integricypta fergusondavie, sp. n.; Integricypta teosoonkimae, sp. n.; Integricypta shirinae, sp. n.; Integricypta hoyuenhoeae, sp. n. (Mycetophilinae). The previously described species are Metanepsia malaysiana Kallweit, Eumanota racola Soli, Parempheriella defectiva (Edwards), Neoempheria dizonalis (Edwards) (all known from Sumatra and/or the Malaysian peninsula), and Chalastonepsia hokkaidensis Kallweit a species spread in east Asia. The mycomyine genus Vecella Wu & Yang is here proposed as a new synonym to Parempheriella, with P. guadunana (Wu & Yang), n. comb. corresponding to an additional Palearctic species of Parempheriella. Barcodes for a second set of 1,493 Singapore mycetophilid specimens suggest the presence of an additional 18 MOTUs. We thus estimate that approximately 85% of all the Singapore species that routinely enter Malaise traps are identified or described here. The revision concludes with a discussion of the biogeography and generic composition of the mycetophilid fauna at the southern end of the Malay Peninsula. Zusammenfassung"Open-ended" oder "Dark Taxa" sind artenreiche Klade, die so abundant und arteinreich sind, dass die herkommlichen taxonomischen Methoden angesichts der gro{beta}en Anzahl von Exemplaren und Arten nicht gut funktionieren. Neue Ansatze, die auf das Vorsortierung von Exemplaren mit DNA Barcodes bis zum Artniveau basieren, erlauben es jetzt aber solche Taxa zu revidieren. Allerdings kann auch mit DNA Barcodes, nur die Fauna eines vergleichsweise kleinen Gebietes bearbeiten werden, weil fur die meisten Lander und biogeografischen Regionen zu viele Exemplare und Arten abgedeckt werden mussten. Wir demonstrieren hier wie eine solche Revision durchgefuhrt werden kann. Wir revidieren hier die Pilzmucken (Diptera: Mycetophilidae) von Singapur, die mit Malaisefallen gefangen werden konnen. Das hier uberarbeitete Material stammt aus 496 Malaise-Fallenproben, die mit 71 Malaise-Fallen an 107 Sammelstellen in verschiedenen Habitaten gefangen wurden: Mangroven, Sumpfwalder, Su{beta}wassersumpfe, Primarregenwalder und Sekundarwalder. Basierend auf molekularen und morphologischen Daten fur mehr als 1454 Tiere grenzen wir 120 Arten mit molekularen und morphologischen Daten ab, wobei nur 5 dieser Arten bereits beschrieben sind. Die verbleibenden 115 werden hier beschrieben. Allerdings benennen wir nur 98 Arten, da fur zwei Arten molekulare Daten fehlen und fur 14 weitere Arten derzeit nur Weibchen bekannt sind. Daher konnen wir derzeit keine zufriedenstellende morphologische Diagnose erstellen. Daruber hinaus fehlen molekulare Daten fur drei Arten (Epicypta sp. A, Epicypta sp. B und Neoempheria sp. H). Was die Artgrenzen betrifft, so stimmen die molekularen und morphologischen Daten in den meisten Fallen uberein (match ratio: 95% fur 3% MOTUs). Eine noch hohere "match ratio" von 99% wird fur 5% und ABGD MOTUs (P=0,060) beobachtet. Insgesamt ist das Verhaltnis zwischen unbeschrieben und beschrieben erstaunlich hoch (20:1), und die Uberarbeitung der singapurer Fauna erhoht die Anzahl der beschriebenen Arten in der Orientalischen Region um uber 25%. Dies unterstreicht den Ausma{beta} des "taxonomic impediments" fur Pilzmucken. Die meisten der Mycetophilidenarten in Singapur gehoren zu drei von 22 Gattungen - Neoempheria Osten-Sacken (31 Arten), Epicypta Winnertz (29 Arten) und Manota Williston (14 Arten), aber wir beschreiben hier auch eine neue Gattung, Integricypta, gen. n. basierend auf drei Arten. Die Gattung gehort zu den Mycetophilinae Mycetophilini und ist die mutma{beta}liche Schwestergruppe von Aspidionia Colless. Die sequenzierten, illustrierten und benannten Arten sind: Leptomorphus rafflesi, sp. n.; Monoclona simhapura, sp. n.; Azana demeijeri, sp. n.; Azana leekongchiani, sp. n. (Sciophilinae); Tetragoneura crawfurdi, sp. n.; Tetragoneura chola, sp. n.; Tetragoneura dayuan, sp. n.; Tetragoneura farquhari, sp. n.; Ectrepesthoneura johor, sp. n. (Tetragoneurinae); Mohelia zubirsaidi, sp. n.; Allactoneura tumasik, sp. n.; Allactoneura limbosengi, sp. n.; Manota banzu, sp. n.; Manota tantocksengi, sp. n.; Manota bukittimah, sp. n.; Manota chiamassie, sp. n.; Manota danmaxi, sp. n.; Manota mahuan, sp. n.; Manota temenggong, sp. n.; Clastobasis sritribuana, sp. n.; Clastobasis bugis, sp. n.; Clastobasis oranglaut, sp. n. (Leiinae); Parempheriella mait, sp. n.; Parempheriella longyamen, sp. n.; Parempheriella peranakan, sp. n.; Mycomya sachmatich, sp. n.; Neoempheria merlio, sp. n.; Neoempheria sabana, sp. n.; Neoempheria sangabo, sp. n.; Neoempheria shicheng, sp. n.; Neoempheria ujong, sp. n.; Neoempheria subaraji, sp. n.; Neoempheria kokoiyeeae, sp. n.; Neoempheria mandai, sp. n.; Neoempheria malacca, sp. n.; Neoempheria sinkapho, sp. n.; Neoempheria singapura, sp. n.; Neoempheria xinjiapo, sp. n.; Neoempheria puluochung, sp. n.; Neoempheria merdeka, sp. n.; Neoempheria neesoon, sp. n.; Neoempheria pulau, sp. n.; Neoempheria cinkappur, sp. n.; Neoempheria temasek, sp. n.; Neoempheria polunini, sp. n.; Neoempheria fajar, sp. n.; Neoempheria riatanae, sp. n. (Mycomyinae); Brachycampta glorialimae, sp. n.; Brachycampta murphyi, sp. n.; Brachycampta limtzepengi, sp. n.; Rymosia teopohlengi, sp. n.; Exechia tanswiehiani, sp. n.; Exechia alinewongae, sp. n.; Mycetophila chngseoktinae, sp. n.; Mycetophila georgettechenae, sp. n.; Mycetophila aishae, sp. n.; Platyprosthiogyne phanwaithongae, sp. n.; Platyprosthiogyne gohsookhimae, sp. n.; Platyprosthiogyne rahimahae, sp. n.; Platyprosthiogyne lynetteseahae, sp. n.; Platyprosthiogyne neilaae, sp. n.; Platyprosthiogyne snehalethaae, sp. n.; Platurocypta adeleneweeae, sp. n.; Platurocypta tanhoweliangi, sp. n.; Epicypta constancesingamae, sp. n.; Epicypta jennylauae, sp. n.; Epicypta limchiumeiae, sp. n.; Epicypta janetyeeae, sp. n.; Epicypta kohkhenglianae, sp. n.; Epicypta daintoni, sp. n.; Epicypta holltumi, sp.n.; Epicypta ridleyi, sp. n.; Epicypta chezaharaae, sp. n.; Epicypta tanjiakkimi, sp. n.; Epicypta gehminae, sp. n.; Epicypta jackieyingae, sp. n.; Epicypta khatijunae, sp. n.; Epicypta purchoni, sp. n.; Epicypta foomaoshengi, sp. n.; Epicypta ganengsengi, sp. n.; Epicypta nanyangu, sp. n.; Epicypta nus, sp. n.; Epicypta peterngi, sp. n.; Epicypta maggielimae, sp. n.; Epicypta yupeigaoae, sp. n.; Epicypta annwee, sp. n.; Epicypta wallacei, sp. n.; Epicypta lamtoongjini, sp. n.; Epicypta catherinelimae, sp. n.; Epicypta grootaerti, sp. n.; Epicypta joaquimae, sp. n.; Aspidionia cheesweeleeae, sp. n.; Aspidionia janetjesudasonae, sp. n.; Aspidionia fatimahae, sp. n.; Integricypta fergusondavie, sp. n.; Integricypta teosoonkimae, sp. n.; Integricypta shirinae, sp. n.; Integricypta hoyuenhoeae, sp. n. (Mycetophilinae). Die Tiere, die zu den bereits beschriebenen Arten gehoren, gehoren zu den folgenden Arten: Metanepsia malaysiana Kallweit, Eumanota racola Soli, Parempheriella defectiva (Edwards), Neoempheria dizonalis (Edwards) (alle Arten sind derzeit aus Sumatra und/oder der malaysischen Halbinsel bekannt), und Chalastonepsia hokkaidensis Kallweit, eine in Ostasien verbreitete Art. Die Gattung Vecella Wu & Yang wird hier als neues Synonym fur Parempheriella vorgeschlagen, wobei P. guadunana (Wu & Yang), n. comb., wobei die Gattung damit eine zusatzlichen palaarktischen Art erhalt. Die DNA Barcodes fur eine zweite Stichprobe mit 1.493 Pilzmucken deuten darauf hin, dass in Singapur 18 zusatzliche Arten mit Malaisefallen gefangen werden konnen. Es sieht aber dennoch so aus, als wurden wir bereits hier circa 85% aller Arten beschreiben, die regelma{beta}ig in Malaise-Fallen geraten. Die Revision endet mit einer Diskussion der Biogeographie und taxonomische Zusammensetzung der Mycetophilidenfauna im sudlichen Teil der Malaiischen Halbinsel.

zoology↗
bioRxiv2023

"Dark taxonomy": a new protocol for overcoming the taxonomic impediments for dark taxa and broadening the taxon base for biodiversity assessment

We are entering the 6th mass extinction with little data for "dark taxa" although they comprise most species. Much of the neglect is due to the fact that conventional taxonomic methods struggle with handling thousands of specimens belonging to hundreds of species. We thus here propose a new strategy that we call "dark taxonomy." It addresses (1) taxonomic impediments, (2) lack of biodiversity baselines, (3) and low impact of revisionary research. Taxonomic impediments are reduced by carrying out revisions at small geographic scales to keep the number of specimens low. The risk of taxonomic error is kept low by delimiting species based on two types of data. We then show that dark taxonomy can yield important biodiversity baseline data because it uses samples obtained with biomonitoring traps. Lastly, we argue that the impact of research can be improved by publishing two manuscripts addressing different readerships. The principles of dark taxonomy are illustrated by our taxonomic treatment of Singapores fungus gnats (Mycetophilidae) based only on Malaise trap samples. We show that a first batch of specimens (N=1,454) contains 120 species, of which 115 are new to science thus reducing taxonomic impediments by increasing the number of described Oriental species by 25%. Species delimitation started with using DNA barcodes to estimate the number of MOTUs before "LIT" (Large-scale Integrative Taxonomy) was used to obtain the species boundaries for the 120 species by integrating morphological and molecular data. To test the taxonomic completeness of the revision, we then analyzed a second batch of 1,493 specimens and found that >97% belonged to the 120 species described based on the first batch. Indeed, the second batch only contained 18 new and rare MOTUs; i.e. our study suggests that a single revision can simultaneously yield the names for all important species and relevant biodiversity baseline data. Overall, we believe that "dark taxonomy" can quickly ready a large unknown taxon for biomonitoring.

zoology↗
bioRxiv2022

Network analysis with either Illumina or MinION reveals that detecting vertebrate species requires metabarcoding of iDNA from a diverse fly community

Metabarcoding of vertebrate DNA obtained from invertebrates (iDNA) has been used to survey vertebrate communities, but we here show that it can also be used to study species interactions between invertebrates and vertebrates in a spatial context. We sampled the dung and carrion fly community of a swamp forest remnant along a disturbance gradient (10 sites: 80-310m from a road). Approximately, 60% of the baited 407 flies yield 294 vertebrate identifications based on two COI fragments and 16S sequenced with Illumina and/or MinION. A bipartite network analysis finds no specialization in the interaction between flies and vertebrate species, but a spatial analysis revealed that surprisingly 18 of the 20 vertebrate species can be detected within 150m of the road. We show that the fly community sourced for iDNA was unexpectedly rich (24 species, 3 families) and carried DNA for mammals, birds, and reptiles. They included common and rare ground-dwelling (e.g., wild boar, Sunda pangolin), and arboreal species (e.g., long-tailed macaque, Raffles banded langur) as well as small bodied vertebrates (skinks, rats). All of our results were obtained with a new, greatly simplified iDNA protocol that eliminates DNA extraction by obtaining template directly through dissolving feces and regurgitates from individual flies with water. Lastly, we show that MinION- and Illumina-based metabarcoding yield similar results. Overall, flies from several families (calliphorids, muscids and sarcophagids) should be used in iDNA surveys because we show that uncommon fly species carry the signal for several vertebrate species that are otherwise difficult to detect with iDNA.

ecology↗
bioRxiv2022

Global convergence of dominance and neglect in flying insect diversity

Most of arthropod biodiversity is unknown to science. For this reason, it has been unclear whether insect communities around the world are dominated by the same or different taxa. This question can be answered through standardized sampling of biodiversity followed by estimation of species diversity and community composition with DNA sequences. This approach is here applied to flying insects sampled by 39 Malaise traps placed in five biogeographic regions, eight countries, and numerous habitats (>220,000 specimens belonging to >25,000 species in 463 families). Unexpectedly, we find that 20 insect families account for >50% of local species diversity regardless of continent, climatic region, and habitat type. These consistent differences in family-level dominance explain two-thirds of variation in community composition despite massive levels of species turnover, with most species (>97%) in the top 20 families encountered at a single site only. Alarmingly, the same families that dominate global insect diversity also suffer from extreme taxonomic neglect with little signs of increasing activities in recent years. Tackling the biodiversity of these "dark taxa" thereby emerges as an urgent priority because the arthropod groups comprising most of the global flying insect diversity are particularly poorly known.

ecology↗
bioRxiv2021

Riding into the future on a fly: toward a better understanding of phoresy and avian lice evolution (Phthiraptera) by screening bird carcasses for phoretic lice on hippoboscid flies (Diptera)

Many phoretic relationships between insects are understudied because of taxonomic impediments. We here illustrate for avian lice riding on hippoboscid flies how new natural history data on phoretic relationships can be acquired quickly with NGS barcoding. Most avian lice are host-specific, but some can arrive on new hosts by riding hippoboscid flies that feed on bird blood. Our summary of the literature yielded 254 published records which we here show to belong to two large and 13 small interaction networks for birds, flies, and lice. In order to generate new records, we then developed a new protocol based on screening bird carcasses sourced by citizen scientists. The inspection of 131 carcasses from Singapore lead to the first record of a Guimaraesiella louse species riding on Ornithoica momiyamai flies collected from a pitta carcass. Phoresy may explain why this louse species is now known from three phylogenetically disparate hosts (Pitta moluccensis, Ficedula zanthopygia; Pardaliparus elegans). A second new case of phoresy enhances a large interaction network dominated by Ornithophila metallica, a cosmopolitan and polyphagous hippoboscid fly species. Overall, we argue that many other two- and three-way phoretic relationships between arthropods (e.g., mites, pseudoscorpiones, beetles, flies) can be resolved using cost-effective large-scale NGS barcoding, which can be used to pre-sort specimens for taxonomic revision and thus partially overcome some taxonomic impediments.

evolutionary biology↗
bioRxiv2020

Mangroves are an overlooked hotspot of insect diversity despite low plant diversity

We here compare the tropical arthropod fauna across a freshwater swamp and six different forest types (rain-, swamp, dry-coastal, urban, freshwater swamp, mangroves) based on 140,000 barcoded specimens belonging to ca. 8,500 species. Surprisingly, we find that mangroves, a globally imperiled habitat that had been expected to be species-poor for insects, are an overlooked hotspot for insect diversity despite having low plant diversity. Our study reveals a species-rich mangrove insect fauna (>3,000 species) that is distinct (>50% of species are mangrove-specific), and has high species turnover across Southeast and East Asia. For most habitats, plant diversity is a good predictor for insect diversity, but mangroves are an exception and compensate for a comparatively low number of phytophagous and fungivorous insect species by supporting an unusually rich community of predators whose larvae feed in the productive mudflats. For the remaining tropical habitats, the insect communities have diversity patterns that are largely congruent across guilds. The discovery of such a sizeable and distinct insect fauna in a globally threatened habitat underlines how little is known about global insect biodiversity.

ecology↗
bioRxiv2020

Repurposing of KLF5 activates a cell cycle signature during the progression from Barrett's oesophagus to oesophageal adenocarcinoma.

Oesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths and yet compared to other common cancers, we know relatively little about the underlying molecular mechanisms. Barretts oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the specific events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies of BO and OAC and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin in OAC cells to directly regulate cell cycle genes specifically in OAC. Our findings have potential prognostic significance as the survival of patients with high expression of KLF5 target genes is significantly lower. We have provided new insights into the gene expression networks in OAC and the mechanisms behind progression to OAC, chiefly the repurposing of KLF5 for novel regulatory activity in OAC.

cancer biology↗
bioRxiv2018

Identification of a primitive intestinal transcription factor network shared between oesophageal adenocarcinoma and its pre-cancerous precursor state.

Oesophageal adenocarcinoma (OAC) is one of the most frequent causes of cancer deaths and yet compared to other common cancers, we know relatively little about the molecular composition of this tumour type. To further our understanding of this cancer we have used open chromatin profiling to decipher the transcriptional regulatory networks that are operational in OAC. We have uncovered a transcription factor network that is usually found in primitive intestinal cells during embryonic development, centred on HNF4A and GATA6. These transcription factors work together to control the OAC transcriptome. Importantly, we show that this network is activated in Barretts oesophagus, the putative precursor state to OAC thereby providing novel molecular evidence in support of stepwise malignant transition. Furthermore, we show that HNF4A alone, is sufficient to drive chromatin opening and activation of a Barretts-like chromatin signature when expressed in normal human epithelial cells. Collectively, these data provide a new way to categorise OAC at a genome scale and implicate HNF4A activation as a potential pivotal event in regulating its malignant transition from healthy cells.

cancer biology↗