RESUMO
It is well evidenced that South Africa is characterised by extreme socioeconomic inequality, which is strongly racialised. We offer an original sociological perspective, which departs from established perspectives considering the dynamics of vulnerability and poverty to focus on the structuring of classed and racialised privilege. We map how stocks of economic, cultural, and social capital intersect to generate systematic and structural inequalities in the country and consider how far these are associated with fundamental racial divides. To achieve this, we utilise rich, nationally representative data from the National Income Dynamics Study and employ Multiple Correspondence Analysis to construct a model of South African 'social space'. Our findings underscore how entrenched racial divisions remain within South Africa, with White people being overwhelmingly located in the most privileged positions. However, our cluster analysis also indicates that forms of middle-class privilege percolate beyond a core of the 8% of the population that is white. We emphasise how age divisions are associated with social capital accumulation. Our cluster analysis reveals that trust levels increase with economic and cultural capital levels within younger age groups and could therefore come to intensify social and racial divisions.
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We previously identified Wiz in a mouse screen for epigenetic modifiers. Due to its known association with G9a/GLP, Wiz is generally considered a transcriptional repressor. Here, we provide evidence that it may also function as a transcriptional activator. Wiz levels are high in the brain, but its function and direct targets are unknown. ChIP-seq was performed in adult cerebellum and Wiz peaks were found at promoters and transcription factor CTCF binding sites. RNA-seq in Wiz mutant mice identified genes differentially regulated in adult cerebellum and embryonic brain. In embryonic brain most decreased in expression and included clustered protocadherin genes. These also decreased in adult cerebellum and showed strong Wiz ChIP-seq enrichment. Because a precise pattern of protocadherin gene expression is required for neuronal development, behavioural tests were carried out on mutant mice, revealing an anxiety-like phenotype. This is the first evidence of a role for Wiz in neural function.
Assuntos
Comportamento Animal , Fator de Ligação a CCCTC/metabolismo , Cerebelo/fisiologia , Regulação da Expressão Gênica , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Regiões Promotoras Genéticas , Animais , Sítios de Ligação , Imunoprecipitação da Cromatina , Técnicas de Inativação de Genes , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Ligação Proteica , Análise de Sequência de DNARESUMO
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.
Assuntos
Metilação de DNA , Retrovirus Endógenos/genética , Haploinsuficiência , Histona-Lisina N-Metiltransferase/genética , Herança Paterna , Animais , Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Camundongos , Fenótipo , Locos de Características Quantitativas , Retroelementos , Espermatozoides/química , Sequenciamento Completo do GenomaRESUMO
More than one-half billion people are obese, and despite progress in genetic research, much of the heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of triggering obesity in a non-Mendelian, "on/off" manner. Trim28(+/D9) mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-"on" state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine.
Assuntos
Epigênese Genética , Haploinsuficiência , Proteínas Nucleares/genética , Obesidade/genética , Proteínas Repressoras/genética , Magreza/genética , Adolescente , Animais , Índice de Massa Corporal , Criança , Pré-Escolar , Humanos , Camundongos , Inquéritos Nutricionais , Polimorfismo Genético , Proteína 28 com Motivo TripartidoRESUMO
Reporting in Developmental Cell, Shea et al. (2015) show, using an inbred mouse strain, that "epivariation"-stochastic individual differences in DNA methylation-is a much greater contributor to the sperm methylome than is diet. They conclude that DNA methylation is not the mechanism underlying the dietary reprogramming of offspring phenotype.
Assuntos
DNA Ribossômico/genética , Epigênese Genética/genética , Variação Genética , Genoma/genética , Espermatozoides/metabolismo , Animais , MasculinoRESUMO
Transposable elements (TEs) have been active in the mammalian genome for millions of years and the silencing of these elements in the germline is important for the survival of the host. Mice carrying reporter transgenes can be used to model transcriptional silencing. A mutagenesis screen for modifiers of epigenetic gene silencing produced a line with a mutation in Trim33; the mutants displayed increased expression of the reporter transgene. ChIP-seq of Trim33 in testis revealed 9,109 peaks, mostly at promoters. This is the first report of ChIP-seq for Trim33 in any tissue. Comparison with ENCODE datasets showed that regions of high read density for Trim33 had high read density for histone marks associated with transcriptional activity and mapping to TE consensus sequences revealed Trim33 enrichment at RLTR10B, the LTR of one of the youngest retrotransposons in the mouse genome, MMERVK10C. We identified consensus sequences from the 266 regions at which Trim33 ChIP-seq peaks overlapped RLTR10B elements and found a match to the A-Myb DNA-binding site. We found that TRIM33 has E3 ubiquitin ligase activity for A-MYB and regulates its abundance. RNA-seq revealed that mice haploinsufficient for Trim33 had altered expression of a small group of genes in the testis and the gene with the most significant increase was found to be transcribed from an upstream RLTR10B. These studies provide the first evidence that A-Myb has a role in the actions of Trim33 and suggest a role for both A-Myb and Trim33 in the arms race between the transposon and the host. This the first report of any factor specifically regulating RLTR10B and adds to the current literature on the silencing of MMERVK10C retrotransposons. This is also the first report that A-Myb has a role in the transcription of any retrotransposon.
Assuntos
Inativação Gênica , Retroelementos/genética , Testículo/metabolismo , Fatores de Transcrição/metabolismo , Animais , Genoma , Histonas/genética , Histonas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Ligação Proteica , Proteínas Proto-Oncogênicas c-myb/metabolismo , Retroviridae/genética , Sequências Repetidas Terminais , Transativadores/metabolismo , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: Phenotypic variability among inbred littermates reared in controlled environments remains poorly understood. Metastable epialleles refer to loci that intrinsically behave in this way and a few examples have been described. They display differential methylation in association with differential expression. For example, inbred mice carrying the agouti viable yellow (A (vy) ) allele show a range of coat colours associated with different DNA methylation states at the locus. The availability of next-generation sequencing, in particular whole genome sequencing of bisulphite converted DNA, allows us, for the first time, to search for metastable epialleles at base pair resolution. RESULTS: Using whole genome bisulphite sequencing of DNA from the livers of five mice from the A (vy) colony, we searched for sites at which DNA methylation differed among the mice. A small number of loci, 356, were detected and we call these inter-individual Differentially Methylated Regions, iiDMRs, 55 of which overlap with endogenous retroviral elements (ERVs). Whole genome resequencing of two mice from the colony identified very few differences and these did not occur at or near the iiDMRs. Further work suggested that the majority of ERV iiDMRs are metastable epialleles; the level of methylation was maintained in tissue from other germ layers and the level of mRNA from the neighbouring gene inversely correlated with methylation state. Most iiDMRs that were not overlapping ERV insertions occurred at tissue-specific DMRs and it cannot be ruled out that these are driven by changes in the ratio of cell types in the tissues analysed. CONCLUSIONS: Using the most thorough genome-wide profiling technologies for differentially methylated regions, we find very few intrinsically epigenetically variable regions that we term iiDMRs. The most robust of these are at retroviral elements and appear to be metastable epialleles. The non-ERV iiDMRs cannot be described as metastable epialleles at this stage but provide a novel class of variably methylated elements for further study.
RESUMO
A recent study finds that changes to transcription and DNA methylation resulting from in utero exposure to environmental endocrine-disrupting chemicals are not inherited across generations.
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Reprogramação Celular/genética , Metilação de DNA/genética , Disruptores Endócrinos , Epigênese Genética , Animais , Metilação de DNA/efeitos dos fármacos , Epigenômica , Humanos , CamundongosRESUMO
BACKGROUND: We recently identified a novel protein, Rearranged L-myc fusion (Rlf), that is required for DNA hypomethylation and transcriptional activity at two specific regions of the genome known to be sensitive to epigenetic gene silencing. To identify other loci affected by the absence of Rlf, we have now analysed 12 whole genome bisulphite sequencing datasets across three different embryonic tissues/stages from mice wild-type or null for Rlf. RESULTS: Here we show that the absence of Rlf results in an increase in DNA methylation at thousands of elements involved in transcriptional regulation and many of the changes occur at enhancers and CpG island shores. ChIP-seq for H3K4me1, a mark generally found at regulatory elements, revealed associated changes at many of the regions that are differentially methylated in the Rlf mutants. RNA-seq showed that the numerous effects of the absence of Rlf on the epigenome are associated with relatively subtle effects on the mRNA population. In vitro studies suggest that Rlf's zinc fingers have the capacity to bind DNA and that the protein interacts with other known epigenetic modifiers. CONCLUSION: This study provides the first evidence that the epigenetic modifier Rlf is involved in the maintenance of DNA methylation at enhancers and CGI shores across the genome.
Assuntos
Alelos , Ilhas de CpG/genética , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Genes Modificadores , Fatores de Transcrição/genética , Animais , Cromatina/metabolismo , DNA/metabolismo , Metilação de DNA/genética , Replicação do DNA/genética , Éxons/genética , Regulação da Expressão Gênica no Desenvolvimento , Loci Gênicos , Fatores de Troca do Nucleotídeo Guanina , Células HEK293 , Histonas/metabolismo , Homozigoto , Humanos , Fígado/embriologia , Fígado/metabolismo , Lisina/metabolismo , Camundongos , Mutação/genética , Especificidade de Órgãos/genética , Ligação Proteica , Fatores de Transcrição/metabolismo , Transcrição GênicaRESUMO
Position-effect variegation of transgene expression is sensitive to the chromatin state. We previously reported a forward genetic screen in mice carrying a variegated α-globin GFP transgene to find novel genes encoding epigenetic regulators. We named the phenovariant strains "Mommes" for modifiers of murine metastable epialleles. Here we report positional cloning of mutations in two Momme strains which result in suppression of variegation. Both strains harbour point mutations in the erythroid transcription factor, Klf1. One (D11) generates a stop codon in the zinc finger domain and a homozygous null phenotype. The other (D45) generates an amino acid transversion (H350R) within a conserved linker between zinc fingers two and three. Homozygous MommeD45 mice have chronic microcytic anaemia which models the phenotype in a recently described family. This is the first genetic evidence that the linkers between the zinc fingers of transcription factors have a function beyond that of a simple spacer.
Assuntos
Efeitos da Posição Cromossômica , Fatores de Transcrição Kruppel-Like/genética , Mutação , alfa-Globinas/genética , Anemia/genética , Animais , Testes Genéticos/métodos , Camundongos , Camundongos Transgênicos/embriologia , Camundongos Transgênicos/genética , Esplenomegalia/genética , Dedos de Zinco/genéticaRESUMO
This review considers the evidence for inheritance across generations of epigenetic marks and how this phenomenon could be exploited in the cattle and sheep industries. Epigenetic marks are chemical changes in the chromosomes that affect the expression of genes and hence the phenotype of the cell and are passed on during mitosis so that the daughter cells have the same chemical changes or epigenetic marks as the parent cell. Although most epigenetic marks are wiped clean in the process of forming a new zygote, some epigenetic marks (epimutations) may be passed on from parent to offspring. The inheritance of epigenetic marks across generations is difficult to prove as there are usually alternative explanations possible. There are few well documented cases, mainly using inbred strains of mice. The epimutations are unstable and revert to wild type after a few generations. Although, there are no known cases in sheep or cattle, it is likely that inherited epimutations occur in these species but it is unlikely that they explain a large part of the inherited or genetic variation. There is limited evidence in mice and rats that an environmental treatment can cause a change in the epigenetic marks of an animal and that this change can be passed on the next generation. If inherited epimutations occur in sheep and cattle, they will already be utilized to some extent by existing genetic improvement programs. It would be possible to modify the statistical models used in the calculation of estimated breeding values to better recognize the variance controlled by epimutations, but it would probably have, at best, a small effect on the rate on genetic (inherited) gain achieved. Although not a genetic improvement, the inheritance of epigenetic marks caused by the environment experienced by the sire offers a new opportunity in sheep and cattle breeding. However, at present we do not know if this occurs or, if it does, what environmental treatment might have a beneficial effect.
RESUMO
BACKGROUND: Krüppel-like Factor 3 (KLF3) is a broadly expressed zinc-finger transcriptional repressor with diverse biological roles. During erythropoiesis, KLF3 acts as a feedback repressor of a set of genes that are activated by Krüppel-like Factor 1 (KLF1). Noting that KLF1 binds α-globin gene regulatory sequences during erythroid maturation, we sought to determine whether KLF3 also interacts with the α-globin locus to regulate transcription. RESULTS: We found that expression of a human transgenic α-globin reporter gene is markedly up-regulated in fetal and adult erythroid cells of Klf3-/- mice. Inspection of the mouse and human α-globin promoters revealed a number of canonical KLF-binding sites, and indeed, KLF3 was shown to bind to these regions both in vitro and in vivo. Despite these observations, we did not detect an increase in endogenous murine α-globin expression in Klf3-/- erythroid tissue. However, examination of murine embryonic fibroblasts lacking KLF3 revealed significant de-repression of α-globin gene expression. This suggests that KLF3 may contribute to the silencing of the α-globin locus in non-erythroid tissue. Moreover, ChIP-Seq analysis of murine fibroblasts demonstrated that across the locus, KLF3 does not occupy the promoter regions of the α-globin genes in these cells, but rather, binds to upstream, DNase hypersensitive regulatory regions. CONCLUSIONS: These findings reveal that the occupancy profile of KLF3 at the α-globin locus differs in erythroid and non-erythroid cells. In erythroid cells, KLF3 primarily binds to the promoters of the adult α-globin genes, but appears dispensable for normal transcriptional regulation. In non-erythroid cells, KLF3 distinctly binds to the HS-12 and HS-26 elements and plays a non-redundant, albeit modest, role in the silencing of α-globin expression.
Assuntos
Células Eritroides/metabolismo , Regulação da Expressão Gênica/genética , Fatores de Transcrição Kruppel-Like/genética , alfa-Globinas/genética , Animais , Sítios de Ligação/genética , Células COS , Linhagem Celular Tumoral , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Células K562 , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Regiões Promotoras Genéticas/genética , Transcrição Gênica/genética , alfa-Globinas/metabolismoRESUMO
An ENU mutagenesis screen to identify novel epigenetic modifiers was established in mice carrying a multi-copy GFP transgene, which is expressed in a variegated manner in erythrocytes and is highly sensitive to epigenetic silencing. The screen has produced mouse mutants of both known modifiers of epigenetic state, such as Dnmt1 and Smarca5, and novel modifiers, such as Smchd1 and Rlf. Here we report two mouse lines generated from the screen, MommeD6 and MommeD20, with point mutations in D14Abb1e. These are the first mouse mutants of D14Abb1e (also known as Fam208a), a gene about which little is known. Heterozygous intercrosses show that homozygous mutants from both the MommeD6 and MommeD20 lines are not viable beyond gastrulation, demonstrating an important role for D14Abb1e in development. We demonstrate that haploinsufficiency for D14Abb1e effects transgene expression at the RNA level. Analysis of the predicted D14Abb1e protein sequence reveals that it contains putative nuclear localisation signals and a domain of unknown function, DUF3715. Our studies reveal that D14Abb1e is localised to the nucleus and is expressed in skin and testes.
Assuntos
Desenvolvimento Embrionário , Proteínas Nucleares/genética , Proteínas/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Núcleo Celular/metabolismo , Eritrócitos/metabolismo , Fluorescência , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Dados de Sequência Molecular , Mutação/genética , Proteínas Nucleares/química , Transporte Proteico , Proteínas/química , Pele/metabolismo , Testículo/metabolismo , TransgenesRESUMO
Much of what we know about the role of epigenetics in the determination of phenotype has come from studies of inbred mice. Some unusual expression patterns arising from endogenous and transgenic murine alleles, such as the Agouti coat color alleles, have allowed the study of variegation, variable expressivity, transgenerational epigenetic inheritance, parent-of-origin effects, and position effects. These phenomena have taught us much about gene silencing and the probabilistic nature of epigenetic processes. Based on some of these alleles, large-scale mutagenesis screens have broadened our knowledge of epigenetic control by identifying and characterizing novel genes involved in these processes.
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Epigênese Genética , Técnicas Genéticas , Modelos Animais , Alelos , Animais , Modelos Animais de Doenças , Feminino , Inativação Gênica , Genes Recessivos , Genótipo , Proteínas de Fluorescência Verde/metabolismo , Homozigoto , Masculino , Camundongos , Camundongos Transgênicos , Modelos Genéticos , Mutagênese , FenótipoRESUMO
When brought into captivity, wild animals can adapt to domestication within 10 generations. Such adaptations may decrease fitness in natural conditions. Many selective pressures are disrupted in captivity, including social behavioral networks. Although lack of sociality in captivity appears to mediate domestication, the underlying mechanisms are not well understood. Additionally, determining the contribution of genetic inheritance vs. transgenerational effects during relaxed selection may provide insight into the flexibility of adaptation. When wild-derived mice kept under laboratory conditions for eight generations were reintroduced to sociality and promiscuity (free mate choice), they adapted within two generations. Fitness assessments between this promiscuous lineage and a monogamous laboratory lineage revealed male-specific effects. Promiscuous-line males had deficits in viability, but a striking advantage in attracting mates, and their scent marks were also more attractive to females. Here, we investigate mechanistic details underlying this olfactory signal and identify a role of major urinary protein (MUP) pheromones. Promiscuous-line males inherit higher MUP expression than monogamous-line males through transgenerational inheritance. Sociality-driven maternal and paternal effects reveal intriguing conflicts among parents and offspring over pheromone expression. MUP up-regulation is not driven by hormone-driven transduction pathways, but rather is associated with reduction in DNA methylation of a CpG dinucleotide in the promoter. This reduction in methylation could enhance transcription by promoting the binding of transcription factor USF1 (upstream stimulatory factor 1). Finally, we experimentally demonstrate that increased MUP expression is a female attractant. These results identify molecular mechanisms guiding domestication and adaptive responses to fluctuating sociality.
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Adaptação Biológica/fisiologia , Animais de Laboratório/fisiologia , Preferência de Acasalamento Animal/fisiologia , Proteínas/metabolismo , Meio Social , Animais , Imunoprecipitação da Cromatina , Epigênese Genética/fisiologia , Feminino , Masculino , Exposição Materna , Camundongos , Radioimunoensaio , Testosterona/sangueRESUMO
BACKGROUND: We have used a sensitized ENU mutagenesis screen to produce mouse lines that carry mutations in genes required for epigenetic regulation. We call these lines Modifiers of murine metastable epialleles (Mommes). RESULTS: We report a basic molecular and phenotypic characterization for twenty of the Momme mouse lines, and in each case we also identify the causative mutation. Three of the lines carry a mutation in a novel epigenetic modifier, Rearranged L-myc fusion (Rlf), and one gene, Rap-interacting factor 1 (Rif1), has not previously been reported to be involved in transcriptional regulation in mammals. Many of the other lines are novel alleles of known epigenetic regulators. For two genes, Rlf and Widely-interspaced zinc finger (Wiz), we describe the first mouse mutants. All of the Momme mutants show some degree of homozygous embryonic lethality, emphasizing the importance of epigenetic processes. The penetrance of lethality is incomplete in a number of cases. Similarly ,abnormalities in phenotype seen in the heterozygous individuals of some lines occur with incomplete penetrance. CONCLUSIONS: Recent advances in sequencing enhance the power of sensitized mutagenesis screens to identify the function of previously uncharacterized factors and to discover additional functions for previously characterized proteins. The observation of incomplete penetrance of phenotypes in these inbred mutant mice, at various stages of development, is of interest. Overall, the Momme collection of mouse mutants provides a valuable resource for researchers across many disciplines.
Assuntos
Epigênese Genética , Etilnitrosoureia/farmacologia , Genes Letais , Mutagênese , Mutagênicos/farmacologia , Mutação/efeitos dos fármacos , Alelos , Animais , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Fatores de Troca do Nucleotídeo Guanina , Heterozigoto , Homozigoto , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Fenótipo , Proteínas de Ligação a Telômeros/genética , Fatores de Transcrição/genéticaRESUMO
Studies using human and mouse cells have revealed some changes to non-telomeric chromatin and gene expression in response to abnormally short telomeres. To investigate this further, we studied the effect of inheriting shorter telomeres on transcription and genetic stability at non-telomeric sites in the mouse. Using multiple generations of Terc knockout mice, we show that inheriting shorter telomeres from one parent increases the likelihood of transcriptional silencing at a non-telomeric green fluorescent protein (GFP) transgene inherited from the other parent. In these cases, silencing must occur at or after zygote formation. In grand-offspring from a G3 Terc (-/-) parent, transgene expression was further reduced and associated with increased DNA methylation and, surprisingly, reduced copy number at the transgene array. In these cases, the transgene had been passed through the germline of a Terc-compromised parent, providing an opportunity for meiotic events. Furthermore, genome-wide microarray analysis of copy number variations revealed greater genetic instability in G3 Terc (-/-) mice than detected in wild-type mice of the same genetic background. Our results have implications for the molecular mechanisms underlying premature-ageing syndromes, such as dyskeratosis congenita. In autosomal-dominant dyskeratosis congenita, progressive telomere shortening is seen as it passes down the generations, and this is associated with anticipation, i.e. the disease becomes more severe earlier. The underlying mechanism is not known, but has been considered to be simply associated with decreases in telomere length. Epigenetic and/or genetic changes at non-telomeric regions could, in theory, be involved.
Assuntos
Epigênese Genética , Telômero/genética , Animais , Variações do Número de Cópias de DNA , Metilação de DNA , Disceratose Congênita/genética , Feminino , Regulação da Expressão Gênica , Inativação Gênica , Loci Gênicos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Endogamia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise em Microsséries , Linhagem , RNA/genética , Telomerase/genética , TransgenesRESUMO
Observations of inherited phenotypes that cannot be explained solely through genetic inheritance are increasing. Evidence points to transmission of non-DNA molecules in the gamete as mediators of the phenotypes. However, in most cases it is unclear what the molecules are, with DNA methylation, chromatin proteins, and small RNAs being the most prominent candidates. From a screen to generate novel mouse mutants of genes involved in epigenetic reprogramming, we produced a DNA methyltransferase 3b allele that is missing exon 13. Mice that are homozygous for the mutant allele have smaller stature and reduced viability, with particularly high levels of female post-natal death. Reduced DNA methylation was also detected at telocentric repeats and the X-linked Hprt gene. However, none of the abnormal phenotypes or DNA methylation changes worsened with multiple generations of homozygous mutant inbreeding. This suggests that in our model the abnormalities are reset each generation and the processes of transgenerational epigenetic reprogramming are effective in preventing their inheritance.