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Article ; Online: Modelling Neurological Diseases in Large Animals: Criteria for Model Selection and Clinical Assessment.

Eaton, Samantha L / Murdoch, Fraser / Rzechorzek, Nina M / Thompson, Gerard / Hartley, Claudia / Blacklock, Benjamin Thomas / Proudfoot, Chris / Lillico, Simon G / Tennant, Peter / Ritchie, Adrian / Nixon, James / Brennan, Paul M / Guido, Stefano / Mitchell, Nadia L / Palmer, David N / Whitelaw, C Bruce A / Cooper, Jonathan D / Wishart, Thomas M

Cells

2022 Volume 11, Issue 17

Abstract: Issue: ...

Abstract	Issue:
MeSH term(s)	Animals ; Disease Progression ; Humans ; Mammals ; Models, Animal ; Nervous System Diseases
Language	English
Publishing date	2022-08-25
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11172641
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Transgenerational epigenetic inheritance in health and disease.

Whitelaw, Nadia C / Whitelaw, Emma

Current opinion in genetics & development

2008 Volume 18, Issue 3, Page(s) 273–279

Abstract: Over the past century, patterns of phenotypic inheritance have been observed that are not easily rationalised by Mendel's rules of inheritance. Now that we have begun to understand more about non-DNA based, or 'epigenetic', control of phenotype at the ... ...

Abstract	Over the past century, patterns of phenotypic inheritance have been observed that are not easily rationalised by Mendel's rules of inheritance. Now that we have begun to understand more about non-DNA based, or 'epigenetic', control of phenotype at the molecular level, the idea that the transgenerational inheritance of these epigenetic states could explain non-Mendelian patterns of inheritance has become attractive. There is a growing body of evidence that abnormal epigenetic states, termed epimutations, are associated with disease in humans. For example, in several cases of colorectal cancer, epimutations have been identified that silence the human mismatch repair genes, MLH1 and MSH2. But strong evidence that the abnormal epigenetic states are primary events that occur in the absence of genetic change and are inherited across generations is still absent.
MeSH term(s)	Animals ; Disease/genetics ; Environment ; Epigenesis, Genetic/physiology ; Family Characteristics ; Health ; Humans ; Inheritance Patterns/physiology ; Models, Biological ; Mutation/physiology
Language	English
Publishing date	2008-06
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1077312-5
ISSN	1879-0380 ; 0959-437X
ISSN (online)	1879-0380
ISSN	0959-437X
DOI	10.1016/j.gde.2008.07.001
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Zs.A 3240: Show issues

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Article ; Online: Tuning in to noise: epigenetics and intangible variation.

Whitelaw, Nadia C / Chong, Suyinn / Whitelaw, Emma

Developmental cell

2010 Volume 19, Issue 5, Page(s) 649–650

Abstract: In this special issue of Developmental Cell, we discuss the role of chromatin in phenotypic variation as a counterpoint to the reviews on chromatin dynamics in development and cancer. We highlight some recent work on the role of chromatin in ... ...

Abstract	In this special issue of Developmental Cell, we discuss the role of chromatin in phenotypic variation as a counterpoint to the reviews on chromatin dynamics in development and cancer. We highlight some recent work on the role of chromatin in transcriptional noise in yeast and Caenorhabditis elegans and consider the implications in understanding intangible variation or developmental noise in mammals.
MeSH term(s)	Animals ; Caenorhabditis elegans/genetics ; Chromatin/metabolism ; Epigenesis, Genetic ; Genetic Variation ; Transcription, Genetic ; Yeasts/genetics
Chemical Substances	Chromatin
Language	English
Publishing date	2010-11-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2054967-2
ISSN	1878-1551 ; 1534-5807
ISSN (online)	1878-1551
ISSN	1534-5807
DOI	10.1016/j.devcel.2010.11.001
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Zs.A 5742: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: How lifetimes shape epigenotype within and across generations.

Whitelaw, Nadia C / Whitelaw, Emma

Human molecular genetics

2006 Volume 15 Spec No 2, Page(s) R131–7

Abstract: Despite our detailed characterization of the human genome at the level of the primary DNA sequence, we are still far from understanding the molecular events underlying phenotypic variation. Epigenetic modifications to the DNA sequence and associated ... ...

Abstract	Despite our detailed characterization of the human genome at the level of the primary DNA sequence, we are still far from understanding the molecular events underlying phenotypic variation. Epigenetic modifications to the DNA sequence and associated chromatin are known to regulate gene expression and, as such, are a significant contributor to phenotype. Studies of inbred mice and monozygotic twins show that variation in the epigenotype can be seen even between genetically identical individuals and that this, in some cases at least, is associated with phenotypic differences. Moreover, recent evidence suggests that the epigenome can be influenced by the environment and these changes can last a lifetime. However, we also know that epigenetic states in real-time are in continual flux and, as a result, the epigenome exhibits instability both within and across generations. We still do not understand the rules governing the establishment and maintenance of the epigenotype at any particular locus. The underlying DNA sequence itself and the sequence at unlinked loci (modifier loci) are certainly involved. Recent support for the existence of transgenerational epigenetic inheritance in mammals suggests that the epigenetic state of the locus in the previous generation may also play a role. Over the next decade, many of these processes will be better understood, heralding a greater capacity for us to correlate measurable molecular marks with phenotype and providing the opportunity for improved diagnosis and presymptomatic healthcare.
MeSH term(s)	Animals ; Chromatin/genetics ; DNA Methylation ; DNA Replication/genetics ; Environment ; Epigenesis, Genetic ; Genotype ; Humans ; Mice ; Models, Genetic ; Phenotype ; Stochastic Processes
Chemical Substances	Chromatin
Language	English
Publishing date	2006-10-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddl200
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Zs.A 3469: Show issues

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Article ; Online: Hypomethylation of ERVs in the sperm of mice haploinsufficient for the histone methyltransferase Setdb1 correlates with a paternal effect on phenotype.

Daxinger, Lucia / Oey, Harald / Isbel, Luke / Whitelaw, Nadia C / Youngson, Neil A / Spurling, Alex / Vonk, Kelly K D / Whitelaw, Emma

Scientific reports

2016 Volume 6, Page(s) 25004

Abstract: The number of reports of paternal epigenetic influences on the phenotype of offspring in rodents is increasing but the molecular events involved remain unclear. Here, we show that haploinsufficiency for the histone 3 lysine 9 methyltransferase Setdb1 in ... ...

Abstract	The number of reports of paternal epigenetic influences on the phenotype of offspring in rodents is increasing but the molecular events involved remain unclear. Here, we show that haploinsufficiency for the histone 3 lysine 9 methyltransferase Setdb1 in the sire can influence the coat colour phenotype of wild type offspring. This effect occurs when the allele that directly drives coat colour is inherited from the dam, inferring that the effect involves an "in trans" step. The implication of this finding is that epigenetic state of the sperm can alter the expression of genes inherited on the maternally derived chromosomes. Whole genome bisulphite sequencing revealed that Setdb1 mutant mice show DNA hypomethylation at specific classes of transposable elements in the sperm. Our results identify Setdb1 as a paternal effect gene in the mouse and suggest that epigenetic inheritance may be more likely in individuals with altered levels of epigenetic modifiers.
Language	English
Publishing date	2016--26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep25004
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Article ; Online: Modelling Neurological Diseases in Large Animals

Samantha L. Eaton / Fraser Murdoch / Nina M. Rzechorzek / Gerard Thompson / Claudia Hartley / Benjamin Thomas Blacklock / Chris Proudfoot / Simon G. Lillico / Peter Tennant / Adrian Ritchie / James Nixon / Paul M. Brennan / Stefano Guido / Nadia L. Mitchell / David N. Palmer / C. Bruce A. Whitelaw / Jonathan D. Cooper / Thomas M. Wishart

Cells, Vol 11, Iss 2641, p

Criteria for Model Selection and Clinical Assessment

2022 Volume 2641

Abstract: Issue: The impact of neurological disorders is recognised globally, with one in six people affected in their lifetime and few treatments to slow or halt disease progression. This is due in part to the increasing ageing population, and is confounded by ... ...

Abstract	Issue: The impact of neurological disorders is recognised globally, with one in six people affected in their lifetime and few treatments to slow or halt disease progression. This is due in part to the increasing ageing population, and is confounded by the high failure rate of translation from rodent-derived therapeutics to clinically effective human neurological interventions. Improved translation is demonstrated using higher order mammals with more complex/comparable neuroanatomy. These animals effectually span this translational disparity and increase confidence in factors including routes of administration/dosing and ability to scale, such that potential therapeutics will have successful outcomes when moving to patients. Coupled with advancements in genetic engineering to produce genetically tailored models, livestock are increasingly being used to bridge this translational gap. Approach: In order to aid in standardising characterisation of such models, we provide comprehensive neurological assessment protocols designed to inform on neuroanatomical dysfunction and/or lesion(s) for large animal species. We also describe the applicability of these exams in different large animals to help provide a better understanding of the practicalities of cross species neurological disease modelling. Recommendation: We would encourage the use of these assessments as a reference framework to help standardise neurological clinical scoring of large animal models.
Keywords	neurological disease ; large animal model ; clinical assessment ; model selection criteria ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Biochemical Assessment of Mitochondrial Respiratory Chain Disorders.

Turton, Nadia / Cufflin, Neve / Dewsbury, Mollie / Fitzpatrick, Olivia / Islam, Rahida / Watler, Lowidka Linares / McPartland, Cara / Whitelaw, Sophie / Connor, Caitlin / Morris, Charlotte / Fang, Jason / Gartland, Ollie / Holt, Liv / Hargreaves, Iain P

International journal of molecular sciences

2022 Volume 23, Issue 13

Abstract: Mitochondrial respiratory chain (MRC) disorders are a complex group of diseases whose diagnosis requires a multidisciplinary approach in which the biochemical investigations play an important role. Initial investigations include metabolite analysis in ... ...

Abstract	Mitochondrial respiratory chain (MRC) disorders are a complex group of diseases whose diagnosis requires a multidisciplinary approach in which the biochemical investigations play an important role. Initial investigations include metabolite analysis in both blood and urine and the measurement of lactate, pyruvate and amino acid levels, as well as urine organic acids. Recently, hormone-like cytokines, such as fibroblast growth factor-21 (FGF-21), have also been used as a means of assessing evidence of MRC dysfunction, although work is still required to confirm their diagnostic utility and reliability. The assessment of evidence of oxidative stress may also be an important parameter to consider in the diagnosis of MRC function in view of its association with mitochondrial dysfunction. At present, due to the lack of reliable biomarkers available for assessing evidence of MRC dysfunction, the spectrophotometric determination of MRC enzyme activities in skeletal muscle or tissue from the disease-presenting organ is considered the 'Gold Standard' biochemical method to provide evidence of MRC dysfunction. The purpose of this review is to outline a number of biochemical methods that may provide diagnostic evidence of MRC dysfunction in patients.
MeSH term(s)	Electron Transport ; Humans ; Mitochondrial Diseases/metabolism ; Mitochondrial Membranes/metabolism ; Pyruvic Acid/metabolism ; Reproducibility of Results
Chemical Substances	Pyruvic Acid (8558G7RUTR)
Language	English
Publishing date	2022-07-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23137487
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Article ; Online: Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise.

Whitelaw, Nadia C / Chong, Suyinn / Morgan, Daniel K / Nestor, Colm / Bruxner, Timothy J / Ashe, Alyson / Lambley, Eleanore / Meehan, Richard / Whitelaw, Emma

Genome biology

2010 Volume 11, Issue 11, Page(s) R111

Abstract: Background: Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing ... ...

Abstract	Background: Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process. Results: Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28) show greater coefficients of variance in body weight than their wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals. Conclusions: These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans.
MeSH term(s)	Alleles ; Animals ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA Methyltransferase 3A ; Epigenesis, Genetic ; Epigenomics ; Female ; Gene Silencing ; Genetic Variation ; Genotype ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nuclear Proteins/genetics ; Oligonucleotide Array Sequence Analysis ; Phenotype ; Polymorphism, Single Nucleotide ; Proto-Oncogene Mas ; Repressor Proteins/genetics ; Transcription, Genetic ; Tripartite Motif-Containing Protein 28
Chemical Substances	DNMT3A protein, human ; Dnmt3a protein, mouse ; MAS1 protein, human ; Mas1 protein, mouse ; Nuclear Proteins ; Proto-Oncogene Mas ; Repressor Proteins ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNA Methyltransferase 3A (EC 2.1.1.37) ; Trim28 protein, mouse (EC 2.3.2.27) ; Tripartite Motif-Containing Protein 28 (EC 2.3.2.27)
Language	English
Publishing date	2010-11-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/gb-2010-11-11-r111
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Article ; Online: ENU mutagenesis identifies the first mouse mutants reproducing human β-thalassemia at the genomic level.

Brown, Fiona C / Scott, Nicholas / Rank, Gerhard / Collinge, Janelle E / Vadolas, Jim / Vickaryous, Nicola / Whitelaw, Nadia / Whitelaw, Emma / Kile, Benjamin T / Jane, Stephen M / Curtis, David J

Blood cells, molecules & diseases

2013 Volume 50, Issue 2, Page(s) 86–92

Abstract: Forward genetic screens have been performed in many species to identify phenotypes in specific organ systems. We have undertaken a large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen to identify dominant mutations that perturb erythropoiesis in ... ...

Abstract	Forward genetic screens have been performed in many species to identify phenotypes in specific organ systems. We have undertaken a large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen to identify dominant mutations that perturb erythropoiesis in mice. Mutant mice that displayed an erythrocyte mean cell volume (MCV) greater than three standard deviations from the population mean were identified. Two of these lines, RBC13 and RBC14, displayed a hypochromic, microcytic anemia, accompanied by a marked reticulocytosis, splenomegaly and diminished red cell survival. Timed pregnancies from heterozygous intercrosses revealed that a quarter of the embryos displayed severe anemia and did not survive beyond embryonic day (E) 18.5, consistent with homozygous β-thalassemia. Genetic complementation studies with a β-thalassemia mouse line reproduced the embryonic lethality in compound heterozygotes and a genomic custom capture array and massively parallel sequencing of the β-globin locus identified the causative mutations. The RBC13 line displayed a nonsense mutation at codon 40 in exon 2 of the β-major gene, invoking parallels with the common β(0)39 thalassemia mutation seen in humans. The RBC14 line exhibited a mutation at the polyadenylation signal of the β-major gene, exactly replicating a human β-thalassemia mutation. The RBC13 and RBC14 lines are the first β-thalassemia mouse models that reproduce human β-thalassemia at the genomic level, and as such highlight the power of ENU mutagenesis screens in generating mouse models of human disease.
MeSH term(s)	Animals ; Codon/genetics ; Codon, Nonsense ; Disease Models, Animal ; Erythrocyte Indices ; Ethylnitrosourea ; Exons/genetics ; Female ; Fetal Death/genetics ; Genes, Dominant ; Genes, Lethal ; Genetic Complementation Test ; Genotype ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mutagenesis ; Mutagens ; Polyadenylation/genetics ; Pregnancy ; Spleen/pathology ; beta-Globins/genetics ; beta-Thalassemia/blood ; beta-Thalassemia/embryology ; beta-Thalassemia/genetics ; beta-Thalassemia/pathology
Chemical Substances	Codon ; Codon, Nonsense ; Mutagens ; beta-Globins ; Ethylnitrosourea (P8M1T4190R)
Language	English
Publishing date	2013-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	1237083-6
ISSN	1096-0961 ; 1079-9796
ISSN (online)	1096-0961
ISSN	1079-9796
DOI	10.1016/j.bcmd.2012.09.004
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Zs.A 1138: Show issues

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Article: Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise

Whitelaw, Nadia C / Chong, Suyinn / Morgan, Daniel K / Nestor, Colm / Bruxner, Timothy J / Ashe, Alyson / Lambley, Eleanore / Meehan, Richard / Whitelaw, Emma

Genome biology. 2010 Nov., v. 11, no. 11

2010

Abstract: BACKGROUND: Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing ... ...

Abstract	BACKGROUND: Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process. RESULTS: Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28) show greater coefficients of variance in body weight than their wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals. CONCLUSIONS: These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans.
Keywords	DNA ; G-protein coupled receptors ; abnormal behavior ; body weight ; epigenetics ; gene expression ; gene silencing ; genes ; heterozygosity ; humans ; lipid metabolism ; loss-of-function mutation ; metabolic syndrome ; methyltransferases ; mice ; mutants ; penetrance ; phenotype ; phenotypic variation ; rearing ; transcription (genetics) ; variance
Language	English
Dates of publication	2010-11
Size	p. R111.
Publishing place	BioMed Central
Document type	Article
ZDB-ID	2040529-7
ISSN	1474-760X ; 1465-6914 ; 1465-6906
ISSN (online)	1474-760X ; 1465-6914
ISSN	1465-6906
DOI	10.1186/gb-2010-11-11-r111
Database	NAL-Catalogue (AGRICOLA)

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