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Article ; Online: A program of successive gene expression in mouse one-cell embryos

Maki Asami / Brian Y.H. Lam / Martin Hoffmann / Toru Suzuki / Xin Lu / Naoko Yoshida / Marcella K. Ma / Kara Rainbow / Miodrag Gužvić / Matthew D. VerMilyea / Giles S.H. Yeo / Christoph A. Klein / Anthony C.F. Perry

Cell Reports, Vol 42, Iss 2, Pp 112023- (2023)

2023

Abstract: Summary: At the moment of union in fertilization, sperm and oocyte are transcriptionally silent. The ensuing onset of embryonic transcription (embryonic genome activation [EGA]) is critical for development, yet its timing and profile remain elusive in ... ...

Abstract	Summary: At the moment of union in fertilization, sperm and oocyte are transcriptionally silent. The ensuing onset of embryonic transcription (embryonic genome activation [EGA]) is critical for development, yet its timing and profile remain elusive in any vertebrate species. We here dissect transcription during EGA by high-resolution single-cell RNA sequencing of precisely synchronized mouse one-cell embryos. This reveals a program of embryonic gene expression (immediate EGA [iEGA]) initiating within 4 h of fertilization. Expression during iEGA produces canonically spliced transcripts, occurs substantially from the maternal genome, and is mostly downregulated at the two-cell stage. Transcribed genes predict regulation by transcription factors (TFs) associated with cancer, including c-Myc. Blocking c-Myc or other predicted regulatory TF activities disrupts iEGA and induces acute developmental arrest. These findings illuminate intracellular mechanisms that regulate the onset of mammalian development and hold promise for the study of cancer.
Keywords	CP: Developmental biology ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A survey of the mouse hindbrain in the fed and fasted states using single-nucleus RNA sequencing

Georgina K.C. Dowsett / Brian Y.H. Lam / John A. Tadross / Irene Cimino / Debra Rimmington / Anthony P. Coll / Joseph Polex-Wolf / Lotte Bjerre Knudsen / Charles Pyke / Giles S.H. Yeo

Molecular Metabolism, Vol 53, Iss , Pp 101240- (2021)

2021

Abstract: Objective: The area postrema (AP) and nucleus tractus solitarius (NTS) located in the hindbrain are key nuclei that sense and integrate peripheral nutritional signals and consequently regulate feeding behaviour. While single-cell transcriptomics have ... ...

Abstract	Objective: The area postrema (AP) and nucleus tractus solitarius (NTS) located in the hindbrain are key nuclei that sense and integrate peripheral nutritional signals and consequently regulate feeding behaviour. While single-cell transcriptomics have been used in mice to reveal the gene expression profile and heterogeneity of key hypothalamic populations, similar in-depth studies have not yet been performed in the hindbrain. Methods: Using single-nucleus RNA sequencing, we provide a detailed survey of 16,034 cells within the AP and NTS of mice in the fed and fasted states. Results: Of these, 8,910 were neurons that group into 30 clusters, with 4,289 from mice fed ad libitum and 4,621 from overnight fasted mice. A total of 7,124 nuclei were from non-neuronal cells, including oligodendrocytes, astrocytes, and microglia. Interestingly, we identified that the oligodendrocyte population was particularly transcriptionally sensitive to an overnight fast. The receptors GLP1R, GIPR, GFRAL, and CALCR, which bind GLP1, GIP, GDF15, and amylin, respectively, are all expressed in the hindbrain and are major targets for anti-obesity therapeutics. We characterise the transcriptomes of these four populations and show that their gene expression profiles are not dramatically altered by an overnight fast. Notably, we find that roughly half of cells that express GIPR are oligodendrocytes. Additionally, we profile POMC-expressing neurons within the hindbrain and demonstrate that 84% of POMC neurons express either PCSK1, PSCK2, or both, implying that melanocortin peptides are likely produced by these neurons. Conclusion: We provide a detailed single-cell level characterisation of AP and NTS cells expressing receptors for key anti-obesity drugs that are either already approved for human use or in clinical trials. This resource will help delineate the mechanisms underlying the effectiveness of these compounds and also prove useful in the continued search for other novel therapeutic targets.
Keywords	Area postrema ; Nucleus tractus solitarius ; Gene expression ; Obesity ; Therapeutics ; Internal medicine ; RC31-1245
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression

Stefan Wagner / Daniel I. Brierley / Alasdair Leeson-Payne / Wanqing Jiang / Raffaella Chianese / Brian Y.H. Lam / Georgina K.C. Dowsett / Claudia Cristiano / David Lyons / Frank Reimann / Fiona M. Gribble / Pablo B. Martinez de Morentin / Giles S.H. Yeo / Stefan Trapp / Lora K. Heisler

Molecular Metabolism, Vol 68, Iss , Pp 101665- (2023)

2023

Abstract: Objective: Overweight and obesity are endemic in developed countries, with a substantial negative impact on human health. Medications developed to treat obesity include agonists for the G-protein coupled receptors glucagon-like peptide-1 (GLP-1R; e.g. ... ...

Abstract	Objective: Overweight and obesity are endemic in developed countries, with a substantial negative impact on human health. Medications developed to treat obesity include agonists for the G-protein coupled receptors glucagon-like peptide-1 (GLP-1R; e.g. liraglutide), serotonin 2C (5-HT2CR; e.g, lorcaserin), and melanocortin4 (MC4R) which reduce body weight primarily by suppressing food intake. However, the mechanisms underlying the therapeutic food intake suppressive effects are still being defined and were investigated here. Methods: We profiled PPG neurons in the nucleus of the solitary tract (PPGNTS) using single nucleus RNA sequencing (Nuc-Seq) and histochemistry. We next examined the requirement of PPGNTS neurons for obesity medication effects on food intake by virally ablating PPGNTS neurons. Finally, we assessed the effects on food intake of the combination of liraglutide and lorcaserin. Results: We found that 5-HT2CRs, but not GLP-1Rs or MC4Rs, were widespread in PPGNTS clusters and that lorcaserin significantly activated PPGNTS neurons. Accordingly, ablation of PPGNTS neurons prevented the reduction of food intake by lorcaserin but not MC4R agonist melanotan-II, demonstrating the functional significance of PPGNTS 5-HT2CR expression. Finally, the combination of lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction as compared to either monotherapy. Conclusions: These findings identify a necessary mechanism through which obesity medication lorcaserin produces its therapeutic benefit, namely brainstem PPGNTS neurons. Moreover, these data reveal a strategy to augment the therapeutic profile of the current frontline treatment for obesity, GLP-1R agonists, via coadministration with 5-HT2CR agonists.
Keywords	Lorcaserin ; Liraglutide ; Preproglucagon ; Nucleus tractus solitarii ; Brainstem ; Serotonin 2C receptor ; Internal medicine ; RC31-1245
Subject code	590
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Dax1 modulates ERα-dependent hypothalamic estrogen sensing in female mice

Jose M. Ramos-Pittol / Isabel Fernandes-Freitas / Alexandra Milona / Stephen M. Manchishi / Kara Rainbow / Brian Y. H. Lam / John A. Tadross / Anthony Beucher / William H. Colledge / Inês Cebola / Kevin G. Murphy / Irene Miguel-Aliaga / Giles S. H. Yeo / Waljit S. Dhillo / Bryn M. Owen

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 10

Abstract: Abstract Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin (KISS1)-neuron pulsatility in the arcuate hypothalamic nucleus, while also ... ...

Abstract	Abstract Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin (KISS1)-neuron pulsatility in the arcuate hypothalamic nucleus, while also exerting a surge-like effect on KISS1-neuron activity in the AVPV hypothalamic nucleus. However, a mechanistic basis for this region-specific effect has remained elusive. Our genomic analysis in female mice demonstrate that some processes, such as restraint of KISS1-neuron activity in the arcuate nucleus, may be explained by region-specific estrogen receptor alpha (ERα) DNA binding at gene regulatory regions. Furthermore, we find that the Kiss1-locus is uniquely regulated in these hypothalamic nuclei, and that the nuclear receptor co-repressor NR0B1 (DAX1) restrains its transcription specifically in the arcuate nucleus. These studies provide mechanistic insight into how ERα may control the KISS1-neuron, and Kiss1 gene expression, to couple gonadotropin release to the developmental stage of the oocyte.
Keywords	Science ; Q
Subject code	612
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells

Ming Yang / Tamana Darwish / Pierre Larraufie / Debra Rimmington / Irene Cimino / Deborah A. Goldspink / Benjamin Jenkins / Albert Koulman / Cheryl A. Brighton / Marcella Ma / Brian Y. H. Lam / Anthony P. Coll / Stephen O’Rahilly / Frank Reimann / Fiona M. Gribble

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 20

Abstract: Abstract Even though metformin is widely used to treat type2 diabetes, reducing glycaemia and body weight, the mechanisms of action are still elusive. Recent studies have identified the gastrointestinal tract as an important site of action. Here we used ... ...

Abstract	Abstract Even though metformin is widely used to treat type2 diabetes, reducing glycaemia and body weight, the mechanisms of action are still elusive. Recent studies have identified the gastrointestinal tract as an important site of action. Here we used intestinal organoids to explore the effects of metformin on intestinal cell physiology. Bulk RNA-sequencing analysis identified changes in hexose metabolism pathways, particularly glycolytic genes. Metformin increased expression of Slc2a1 (GLUT1), decreased expression of Slc2a2 (GLUT2) and Slc5a1 (SGLT1) whilst increasing GLUT-dependent glucose uptake and glycolytic rate as observed by live cell imaging of genetically encoded metabolite sensors and measurement of oxygen consumption and extracellular acidification rates. Metformin caused mitochondrial dysfunction and metformin’s effects on 2D-cultures were phenocopied by treatment with rotenone and antimycin-A, including upregulation of GDF15 expression, previously linked to metformin dependent weight loss. Gene expression changes elicited by metformin were replicated in 3D apical-out organoids and distal small intestines of metformin treated mice. We conclude that metformin affects glucose uptake, glycolysis and GDF-15 secretion, likely downstream of the observed mitochondrial dysfunction. This may explain the effects of metformin on intestinal glucose utilisation and food balance.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Global transcriptomic analysis of the arcuate nucleus following chronic glucocorticoid treatment

Jonathan R. Wray / Alison Davies / Charlotte Sefton / Tiffany-Jayne Allen / Antony Adamson / Philip Chapman / Brian Y.H. Lam / Giles S.H. Yeo / Anthony P. Coll / Erika Harno / Anne White

Molecular Metabolism, Vol 26, Iss , Pp 5-

2019 Volume 17

Abstract: Objective: Glucocorticoids (GCs) are widely prescribed medications that are well recognized to cause adverse metabolic effects including hyperphagia, obesity, and hyperglycemia. These effects have been recapitulated in a murine model of GC excess, and we ...

Abstract	Objective: Glucocorticoids (GCs) are widely prescribed medications that are well recognized to cause adverse metabolic effects including hyperphagia, obesity, and hyperglycemia. These effects have been recapitulated in a murine model of GC excess, and we hypothesize that they are mediated, in part, through central mechanisms. This study aimed to identify genes in the hypothalamic arcuate nucleus (ARC) that are altered with GC treatment and evaluate their contribution to GC-induced metabolic abnormalities. Methods: Corticosterone (Cort; 75 μg/ml) was administered in the drinking water to male C57Bl/6J mice for 2 days or 4 weeks. Phenotypic analysis of each group was undertaken and central and peripheral tissues were collected for biochemical and mRNA analyses. Arcuate nuclei were isolated by laser capture microdissection and tissue analyzed by RNA-seq. Results: RNA-seq analysis of ARC tissue from 4 week Cort treated mice revealed 21 upregulated and 22 downregulated genes at a time when mice had increased food intake, expansion of adipose tissue mass, and insulin resistance. In comparison, after 2 days Cort treatment, when the main phenotypic change was increased food intake, RNA-seq identified 30 upregulated and 16 downregulated genes. Within the genes altered at 2 days were a range of novel genes but also those known to be regulated by GCs, including Fkbp5, Mt2, Fam107a, as well as some involved in the control of energy balance, such as Agrp, Sepp1, Dio2, and Nmb. Of the candidate genes identified by RNA-seq, type-II iodothyronine deiodinase (Dio2) was chosen for further investigation as it was increased (2-fold) with Cort, and has been implicated in the control of energy balance via the modulation of hypothalamic thyroid hormone availability. Targeted knockdown of Dio2 in the MBH using AAV-mediated CRISPR-Cas9 produced a mild attenuation in GC-induced brown adipose tissue weight gain, as well as a 56% reduction in the GC-induced increase in Agrp. However, this conferred no protection from GC-induced hyperphagia, obesity, or hyperglycemia. Conclusions: This study identified a comprehensive set of genes altered by GCs in the ARC and enabled the selection of key candidate genes. Targeted knockdown of hypothalamic Dio2 revealed that it did not mediate the chronic GC effects on hyperphagia and hyperglycemia. Keywords: Glucocorticoid, Arcuate nucleus, RNA-Seq, Dio2, CRISPR-Cas9
Keywords	Internal medicine ; RC31-1245
Subject code	616
Language	English
Publishing date	2019-08-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: DEFLATE Compression Algorithm Corrects for Overestimation of Phylogenetic Diversity by Grantham Approach to Single-Nucleotide Polymorphism Classification

Arran Schlosberg / Brian Y. H. Lam / Giles S. H. Yeo / Roderick J. Clifton-Bligh

International Journal of Molecular Sciences, Vol 15, Iss 5, Pp 8491-

2014 Volume 8508

Abstract: Improvements in speed and cost of genome sequencing are resulting in increasing numbers of novel non-synonymous single nucleotide polymorphisms (nsSNPs) in genes known to be associated with disease. The large number of nsSNPs makes laboratory-based ... ...

Abstract	Improvements in speed and cost of genome sequencing are resulting in increasing numbers of novel non-synonymous single nucleotide polymorphisms (nsSNPs) in genes known to be associated with disease. The large number of nsSNPs makes laboratory-based classification infeasible and familial co-segregation with disease is not always possible. In-silico methods for classification or triage are thus utilised. A popular tool based on multiple-species sequence alignments (MSAs) and work by Grantham, Align-GVGD, has been shown to underestimate deleterious effects, particularly as sequence numbers increase. We utilised the DEFLATE compression algorithm to account for expected variation across a number of species. With the adjusted Grantham measure we derived a means of quantitatively clustering known neutral and deleterious nsSNPs from the same gene; this was then used to assign novel variants to the most appropriate cluster as a means of binary classification. Scaling of clusters allows for inter-gene comparison of variants through a single pathogenicity score. The approach improves upon the classification accuracy of Align-GVGD while correcting for sensitivity to large MSAs. Open-source code and a web server are made available at https://github.com/aschlosberg/CompressGV.
Keywords	DEFLATE ; compression ; Grantham ; variation ; sequence alignment ; nsSNP ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	004
Language	English
Publishing date	2014-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Murine neuronatin deficiency is associated with a hypervariable food intake and bimodal obesity

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 15

Abstract: Abstract Neuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim28. Disruption of Trim28 or of members of this network, including neuronatin, results in an unusual phenotype of ... ...

Abstract	Abstract Neuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim28. Disruption of Trim28 or of members of this network, including neuronatin, results in an unusual phenotype of a bimodal body weight. To better characterise this variability, we examined the key contributors to energy balance in Nnat +/−p mice that carry a paternal null allele and do not express Nnat. Consistent with our previous studies, Nnat deficient mice on chow diet displayed a bimodal body weight phenotype with more than 30% of Nnat +/−p mice developing obesity. In response to both a 45% high fat diet and exposure to thermoneutrality (30 °C) Nnat deficient mice maintained the hypervariable body weight phenotype. Within a calorimetry system, food intake in Nnat +/−p mice was hypervariable, with some mice consuming more than twice the intake seen in wild type littermates. A hyperphagic response was also seen in Nnat +/−p mice in a second, non-home cage environment. An expected correlation between body weight and energy expenditure was seen, but corrections for the effects of positive energy balance and body weight greatly diminished the effect of neuronatin deficiency on energy expenditure. Male and female Nnat +/−p mice displayed subtle distinctions in the degree of variance body weight phenotype and food intake and further sexual dimorphism was reflected in different patterns of hypothalamic gene expression in Nnat +/−p mice. Loss of the imprinted gene Nnat is associated with a highly variable food intake, with the impact of this phenotype varying between genetically identical individuals.
Keywords	Medicine ; R ; Science ; Q
Subject code	590
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Nature Portfolio
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Article ; Online: Sirt3 in POMC neurons controls energy balance in a sex- and diet-dependent manner

Mar Quiñones / René Hernández-Bautista / Daniel Beiroa / Violeta Heras / Francisco L. Torres-Leal / Brian Y.H. Lam / Ana Senra / Johan Fernø / Alicia García Gómez-Valadés / Markus Schwaninger / Vincent Prevot / Giles Yeo / Marc Claret / Miguel López / Carlos Diéguez / Omar Al-Massadi / Ruben Nogueiras

Redox Biology, Vol 41, Iss , Pp 101945- (2021)

2021

Abstract: Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuin homologs of the yeast Sir2 gene that has emerged as an important player in the regulation of energy metabolism in peripheral tissues. However, its role in the hypothalamus has not been explored. ... ...

Abstract	Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuin homologs of the yeast Sir2 gene that has emerged as an important player in the regulation of energy metabolism in peripheral tissues. However, its role in the hypothalamus has not been explored. Herein, we show that the genetic inhibition of SIRT3 in the hypothalamic arcuate nucleus (ARC) induced a negative energy balance and improvement of several metabolic parameters. These effects are specific for POMC neurons, because ablation of SIRT3 in POMC, but not in AgRP neurons, decreased body weight and adiposity, increased energy expenditure and brown adipose tissue (BAT) activity, and induced browning in white adipose tissue (WAT). Notably, the depletion of SIRT3 in POMC neurons caused these effects in male mice fed a chow diet but failed to affect energy balance in males fed a high fat diet and females under both type of diets. Overall, we provide the first evidence pointing for a key role of SIRT3 in POMC neurons in the regulation of energy balance.
Keywords	Sirtuins ; Hypothalamus ; brown adipose tissue ; Energy balance ; Adiposity ; Browning ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	590
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Elsevier
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Article ; Online: Heterogeneity of hypothalamic pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing

Brian Y.H. Lam / Irene Cimino / Joseph Polex-Wolf / Sara Nicole Kohnke / Debra Rimmington / Valentine Iyemere / Nicholas Heeley / Chiara Cossetti / Reiner Schulte / Luis R. Saraiva / Darren W. Logan / Clemence Blouet / Stephen O'Rahilly / Anthony P. Coll / Giles S.H. Yeo

Molecular Metabolism, Vol 6, Iss 5, Pp 383-

2017 Volume 392

Abstract: Objective: Arcuate proopiomelanocortin (POMC) neurons are critical nodes in the control of body weight. Often characterized simply as direct targets for leptin, recent data suggest a more complex architecture. Methods: Using single cell RNA sequencing, ... ...

Abstract	Objective: Arcuate proopiomelanocortin (POMC) neurons are critical nodes in the control of body weight. Often characterized simply as direct targets for leptin, recent data suggest a more complex architecture. Methods: Using single cell RNA sequencing, we have generated an atlas of gene expression in murine POMC neurons. Results: Of 163 neurons, 118 expressed high levels of Pomc with little/no Agrp expression and were considered “canonical” POMC neurons (P+). The other 45/163 expressed low levels of Pomc and high levels of Agrp (A+P+). Unbiased clustering analysis of P+ neurons revealed four different classes, each with distinct cell surface receptor gene expression profiles. Further, only 12% (14/118) of P+ neurons expressed the leptin receptor (Lepr) compared with 58% (26/45) of A+P+ neurons. In contrast, the insulin receptor (Insr) was expressed at similar frequency on P+ and A+P+ neurons (64% and 55%, respectively). Conclusion: These data reveal arcuate POMC neurons to be a highly heterogeneous population.Accession Numbers: GSE92707. Author Video: Author Video Watch what authors say about their articles Keywords: POMC, Melanocortin, AGRP, Leptin, Insulin, Hypothalamus, Arcuate nucleus, Gene expression, Neuron, Transcriptome
Keywords	Internal medicine ; RC31-1245
Language	English
Publishing date	2017-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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