Life Sciences Research for Lifelong Health

Publications gavin-kelsey

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Genome-wide base-resolution mapping of DNA methylation in single cells using single-cell bisulfite sequencing (scBS-seq).
Clark SJ, Smallwood SA, Lee HJ, Krueger F, Reik W, Kelsey G

DNA methylation (DNAme) is an important epigenetic mark in diverse species. Our current understanding of DNAme is based on measurements from bulk cell samples, which obscures intercellular differences and prevents analyses of rare cell types. Thus, the ability to measure DNAme in single cells has the potential to make important contributions to the understanding of several key biological processes, such as embryonic development, disease progression and aging. We have recently reported a method for generating genome-wide DNAme maps from single cells, using single-cell bisulfite sequencing (scBS-seq), allowing the quantitative measurement of DNAme at up to 50% of CpG dinucleotides throughout the mouse genome. Here we present a detailed protocol for scBS-seq that includes our most recent developments to optimize recovery of CpGs, mapping efficiency and success rate; reduce hands-on time; and increase sample throughput with the option of using an automated liquid handler. We provide step-by-step instructions for each stage of the method, comprising cell lysis and bisulfite (BS) conversion, preamplification and adaptor tagging, library amplification, sequencing and, lastly, alignment and methylation calling. An individual with relevant molecular biology expertise can complete library preparation within 3 d. Subsequent computational steps require 1-3 d for someone with bioinformatics expertise.

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Nature protocols, 12, 1750-2799, 534-547, 2017

PMID: 28182018

DNA methylation and gene expression changes derived from assisted reproductive technologies can be decreased by reproductive fluids.
Canovas S, Ivanova E, Romar R, García-Martínez S, Soriano-Úbeda C, García-Vázquez FA, Saadeh H, Andrews S, Kelsey G, Coy P

The number of children born since the origin of Assisted Reproductive Technologies (ART) exceeds 5 million. The majority seem healthy, but a higher frequency of defects has been reported among ART-conceived infants, suggesting an epigenetic cost. We report the first whole-genome DNA methylation datasets from single pig blastocysts showing differences between in vivo and in vitro produced embryos. Blastocysts were produced in vitro either without (C-IVF) or in the presence of natural reproductive fluids (Natur-IVF). Natur-IVF embryos were of higher quality than C-IVF in terms of cell number and hatching ability to. RNA-Seq and DNA methylation analyses showed that Natur-IVF embryos have expression and methylation patterns closer to in vivo blastocysts. Genes involved in reprogramming, imprinting and development were affected by culture, with fewer aberrations in Natur-IVF embryos. Methylation analysis detected methylated changes in C-IVF, but not in Natur-IVF, at genes whose methylation could be critical, such as IGF2R and NNAT.

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eLife, 6, 2050-084X, , 2017

PMID: 28134613

Open Access

Establishment and functions of DNA methylation in the germline.
Stewart KR, Veselovska L, Kelsey G

Epigenetic modifications established during gametogenesis regulate transcription and other nuclear processes in gametes, but also have influences in the zygote, embryo and postnatal life. This is best understood for DNA methylation which, established at discrete regions of the oocyte and sperm genomes, governs genomic imprinting. In this review, we describe how imprinting has informed our understanding of de novo DNA methylation mechanisms, highlight how recent genome-wide profiling studies have provided unprecedented insights into establishment of the sperm and oocyte methylomes and consider the fate and function of gametic methylation and other epigenetic modifications after fertilization.

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Epigenomics, , 1750-192X, , 2016

PMID: 27659720

Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity.
Clark SJ, Lee HJ, Smallwood SA, Kelsey G, Reik W

Emerging single-cell epigenomic methods are being developed with the exciting potential to transform our knowledge of gene regulation. Here we review available techniques and future possibilities, arguing that the full potential of single-cell epigenetic studies will be realized through parallel profiling of genomic, transcriptional, and epigenetic information.

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Genome biology, 17, 1474-760X, 72, 2016

PMID: 27091476

Open Access

Pervasive polymorphic imprinted methylation in the human placenta.
Hanna CW, Peñaherrera MS, Saadeh H, Andrews S, McFadden DE, Kelsey G, Robinson WP

The maternal and paternal copies of the genome are both required for mammalian development and this is primarily due to imprinted genes, those that are mono-allelically expressed based on parent-of-origin. Typically, this pattern of expression is regulated by differentially methylated regions (DMRs) that are established in the germline and maintained after fertilisation. There are a large number of germline DMRs that have not yet been associated with imprinting and their function in development is unknown. In this study, we developed a genome-wide approach to identify novel imprinted DMRs in the human placenta, and investigated the dynamics of these imprinted DMRs during development in somatic and extra-embryonic tissues. DNA methylation was evaluated using the Illumina HumanMethylation450 array in 134 human tissue samples, publically available reduced representation bisulfite sequencing in the human embryo and germ cells, and targeted bisulfite sequencing in term placentas. 43 known and 101 novel imprinted DMRs were identified in the human placenta, by comparing methylation between diandric and digynic triploid conceptions in addition to female and male gametes. 72 novel DMRs showed a pattern consistent with placental-specific imprinting and this mono-allelic methylation was entirely maternal in origin. Strikingly, these DMRs exhibited polymorphic imprinted methylation between placental samples. These data suggest that imprinting in human development is far more extensive and dynamic than previously reported and that the placenta preferentially maintains maternal germline-derived DNA methylation.

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Genome research, , 1549-5469, , 2016

PMID: 26769960

Open Access

Parallel single-cell sequencing links transcriptional and epigenetic heterogeneity.
Angermueller C, Clark SJ, Lee HJ, Macaulay IC, Teng MJ, Hu TX, Krueger F, Smallwood SA, Ponting CP, Voet T, Kelsey G, Stegle O, Reik W

We report scM&T-seq, a method for parallel single-cell genome-wide methylome and transcriptome sequencing that allows for the discovery of associations between transcriptional and epigenetic variation. Profiling of 61 mouse embryonic stem cells confirmed known links between DNA methylation and transcription. Notably, the method revealed previously unrecognized associations between heterogeneously methylated distal regulatory elements and transcription of key pluripotency genes.

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Nature methods, , 1548-7105, , 2016

PMID: 26752769

Open Access

Erratum to: Deep sequencing and de novo assembly of the mouse occyte transcriptome define the contribution of transcription to the DNA methylation landscape.
Veselovska L, Smallwood SA, Saadeh H, Stewart KR, Krueger F, Maupetit-Méhouas S, Arnaud P, Tomizawa S, Andrews S, Kelsey G

Genome biology, 16, 1474-760X, 271, 2015

PMID: 26635312

Dynamic changes in histone modifications precede de novo DNA methylation in oocytes.
Stewart KR, Veselovska L, Kim J, Huang J, Saadeh H, Tomizawa SI, Smallwood SA, Chen T, Kelsey G

Erasure and subsequent reinstatement of DNA methylation in the germline, especially at imprinted CpG islands (CGIs), is crucial to embryogenesis in mammals. The mechanisms underlying DNA methylation establishment remain poorly understood, but a number of post-translational modifications of histones are implicated in antagonizing or recruiting the de novo DNA methylation complex. In mouse oogenesis, DNA methylation establishment occurs on a largely unmethylated genome and in nondividing cells, making it a highly informative model for examining how histone modifications can shape the DNA methylome. Using a chromatin immunoprecipitation (ChIP) and genome-wide sequencing (ChIP-seq) protocol optimized for low cell numbers and novel techniques for isolating primary and growing oocytes, profiles were generated for histone modifications implicated in promoting or inhibiting DNA methylation. CGIs destined for DNA methylation show reduced protective H3K4 dimethylation (H3K4me2) and trimethylation (H3K4me3) in both primary and growing oocytes, while permissive H3K36me3 increases specifically at these CGIs in growing oocytes. Methylome profiling of oocytes deficient in H3K4 demethylase KDM1A or KDM1B indicated that removal of H3K4 methylation is necessary for proper methylation establishment at CGIs. This work represents the first systematic study performing ChIP-seq in oocytes and shows that histone remodeling in the mammalian oocyte helps direct de novo DNA methylation events.

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Genes & development, , 1549-5477, , 2015

PMID: 26584620

Open Access

Continuous Histone Replacement by Hira Is Essential for Normal Transcriptional Regulation and De Novo DNA Methylation during Mouse Oogenesis.
Nashun B, Hill PW, Smallwood SA, Dharmalingam G, Amouroux R, Clark SJ, Sharma V, Ndjetehe E, Pelczar P, Festenstein RJ, Kelsey G, Hajkova P

The integrity of chromatin, which provides a dynamic template for all DNA-related processes in eukaryotes, is maintained through replication-dependent and -independent assembly pathways. To address the role of histone deposition in the absence of DNA replication, we deleted the H3.3 chaperone Hira in developing mouse oocytes. We show that chromatin of non-replicative developing oocytes is dynamic and that lack of continuous H3.3/H4 deposition alters chromatin structure, resulting in increased DNase I sensitivity, the accumulation of DNA damage, and a severe fertility phenotype. On the molecular level, abnormal chromatin structure leads to a dramatic decrease in the dynamic range of gene expression, the appearance of spurious transcripts, and inefficient de novo DNA methylation. Our study thus unequivocally shows the importance of continuous histone replacement and chromatin homeostasis for transcriptional regulation and normal developmental progression in a non-replicative system in vivo.

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Molecular cell, , 1097-4164, , 2015

PMID: 26549683

Deep sequencing and de novo assembly of the mouse oocyte transcriptome define the contribution of transcription to the DNA methylation landscape.
Veselovska L, Smallwood SA, Saadeh H, Stewart KR, Krueger F, Maupetit-Méhouas S, Arnaud P, Tomizawa SI, Andrews S, Kelsey G

Previously, a role was demonstrated for transcription in the acquisition of DNA methylation at imprinted control regions in oocytes. Definition of the oocyte DNA methylome by whole genome approaches revealed that the majority of methylated CpG islands are intragenic and gene bodies are hypermethylated. Yet, the mechanisms by which transcription regulates DNA methylation in oocytes remain unclear. Here, we systematically test the link between transcription and the methylome.

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Genome biology, 16, 1474-760X, 209, 0

PMID: 26408185

Open Access

Keeping methylation at bay.
Kelsey G

A hallmark of CpG islands is their unmethylated state, and determining how DNA methylation can invade these elements is therefore important for understanding developmental gene regulation and disease. A new study shows that FBXL10, a protein commonly altered by mutation in leukemia, is part of a mechanism that blocks methylation of CpG islands.

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Nature genetics, 47, 1546-1718, 427-8, 2015

PMID: 25916897

Epigenetics: Cellular memory erased in human embryos.
Reik W,Kelsey G

Nature, 511, 1476-4687, 540-1, 2014

PMID: 25079550

Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity.
Smallwood SA,Lee HJ,Angermueller C,Krueger F,Saadeh H,Peat J,Andrews SR,Stegle O,Reik W,Kelsey G

We report a single-cell bisulfite sequencing (scBS-seq) method that can be used to accurately measure DNA methylation at up to 48.4% of CpG sites. Embryonic stem cells grown in serum or in 2i medium displayed epigenetic heterogeneity, with '2i-like' cells present in serum culture. Integration of 12 individual mouse oocyte datasets largely recapitulated the whole DNA methylome, which makes scBS-seq a versatile tool to explore DNA methylation in rare cells and heterogeneous populations.

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Nature methods, 11, 1548-7105, 817-20, 2014

PMID: 25042786

Open Access

The specification of imprints in mammals.
Hanna CW,Kelsey G

At the heart of genomic imprinting in mammals are imprinting control regions (ICRs), which are the discrete genetic elements that confer imprinted monoallelic expression to several genes in imprinted gene clusters. A characteristic of the known ICRs is that they acquire different epigenetic states, exemplified by differences in DNA methylation, in the sperm and egg, and these imprint marks remain on the sperm- and oocyte-derived alleles into the next generation as a lifelong memory of parental origin. Although there has been much focus on gametic marking of ICRs as the point of imprint specification, recent mechanistic studies and genome-wide DNA methylation profiling do not support the existence of a specific imprinting machinery in germ cells. Rather, ICRs are part of more widespread methylation events that occur during gametogenesis. Instead, a decisive component in the specification of imprints is the choice of which sites of gamete-derived methylation to maintain in the zygote and preimplantation embryo at a time when much of the remainder of the genome is being demethylated. Among the factors involved in this selection, the zinc-finger protein Zfp57 can be regarded as an imprint-specific, sequence-specific DNA binding factor responsible for maintaining methylation at most ICRs. The recent insights into the balance of gametic and zygotic contributions to imprint specification should help understand mechanistic opportunities and constraints on the evolution of imprinting in mammals.

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Heredity, 113, 1365-2540, 176-83, 2014

PMID: 24939713

Open Access

Detailed analysis of the genetic and epigenetic signatures of iPSC-derived mesodiencephalic dopaminergic neurons.
Roessler R, Smallwood SA, Veenvliet JV, Pechlivanoglou P, Peng SP, Chakrabarty K, Groot-Koerkamp MJ, Pasterkamp RJ, Wesseling E, Kelsey G, Boddeke E, Smidt MP, Copray S

Induced pluripotent stem cells (iPSCs) hold great promise for in vitro generation of disease-relevant cell types, such as mesodiencephalic dopaminergic (mdDA) neurons involved in Parkinson's disease. Although iPSC-derived midbrain DA neurons have been generated, detailed genetic and epigenetic characterizations of such neurons are lacking. The goal of this study was to examine the authenticity of iPSC-derived DA neurons obtained by established protocols. We FACS purified mdDA (Pitx3 (Gfp/+) ) neurons derived from mouse iPSCs and primary mdDA (Pitx3 (Gfp/+) ) neurons to analyze and compare their genetic and epigenetic features. Although iPSC-derived DA neurons largely adopted characteristics of their in vivo counterparts, relevant deviations in global gene expression and DNA methylation were found. Hypermethylated genes, mainly involved in neurodevelopment and basic neuronal functions, consequently showed reduced expression levels. Such abnormalities should be addressed because they might affect unambiguous long-term functionality and hamper the potential of iPSC-derived DA neurons for in vitro disease modeling or cell-based therapy.

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Stem cell reports, 2, 2213-6711, 520-33, 2014

PMID: 24749075

Open Access

DNA methylation establishment during oocyte growth: mechanisms and significance.
Tomizawa S,Nowacka-Woszuk J,Kelsey G

DNA methylation in the oocyte has a particular significance: it may contribute to gene regulation in the oocyte and marks specific genes for activity in the embryo, as in the case of imprinted genes. Despite the fundamental importance of DNA methylation established in the oocyte, knowledge of the mechanisms by which it is conferred and how much is stably maintained in the embryo has remained very limited. Next generation sequencing approaches have dramatically altered our views on DNA methylation in oocytes. They have revealed that most methylation occurs in gene bodies in the oocyte. This observation ties in with genetic evidence showing that transcription is essential for methylation of imprinted genes, and is consistent with a model in which DNA methyltransferases are recruited by the histone modification patterns laid down by transcription events. These findings lead to a new perspective that transcription events dictate the placing and timing of methylation in specific genes and suggest a mechanism by which methylation could be coordinated by the events and factors regulating oocyte growth. With these new insights into the de novo methylation mechanism and new methods that allow high resolution profiling of DNA methylation in oocytes, we should be in a position to investigate whether and how DNA methylation errors could arise in association with assisted reproduction technologies or in response to exposure to environmental toxins.

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The International journal of developmental biology, 56, 1696-3547, 867-75, 2012

PMID: 23417409

Open Access

New insights into establishment and maintenance of DNA methylation imprints in mammals.
G Kelsey, R Feil

Fundamental to genomic imprinting in mammals is the acquisition of epigenetic marks that differ in male and female gametes at 'imprinting control regions' (ICRs). These marks mediate the allelic expression of imprinted genes in the offspring. Much has been learnt about the nature of imprint marks, the times during gametogenesis at which they are laid down and some of the factors responsible especially for DNA methylation. Recent work has revealed that transcription and histone modifications are critically involved in DNA methylation acquisition, and these findings allow us to propose rational models for methylation establishment. A completely novel perspective on gametic DNA methylation has emerged from epigenomic profiling. Far more differentially methylated loci have been identified in gametes than known imprinted genes, which leads us to revise the notion that methylation of ICRs is a specifically targeted process. Instead, it seems to obey default processes in germ cells, giving rise to distinct patterns of DNA methylation in sperm and oocytes. This new insight, together with the identification of proteins that preserve DNA methylation after fertilization, emphasizes the key role played by mechanisms that selectively retain differential methylation at imprinted loci during early development. Addressing these mechanisms will be essential to understanding the specificity and evolution of genomic imprinting.

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Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 368, 1609, 20110336, 2013

PMID: 23166397
DOI: 10.1098/rstb.2011.0336

Open Access

DNA methylation at differentially methylated regions of imprinted genes is resistant to developmental programming by maternal nutrition.
E Ivanova, JH Chen, A Segonds-Pichon, SE Ozanne, G Kelsey

The nutritional environment in which the mammalian fetus or infant develop is recognized as influencing the risk of chronic diseases, such as type 2 diabetes and hypertension, in a phenomenon that has become known as developmental programming. The late onset of such diseases in response to earlier transient experiences has led to the suggestion that developmental programming may have an epigenetic component, because epigenetic marks such as DNA methylation or histone tail modifications could provide a persistent memory of earlier nutritional states. One class of genes that has been considered a potential target or mediator of programming events is imprinted genes, because these genes critically depend upon epigenetic modifications for correct expression and because many imprinted genes have roles in controlling fetal growth as well as neonatal and adult metabolism. In this study, we have used an established model of developmental programming-isocaloric protein restriction to female mice during gestation or lactation-to examine whether there are effects on expression and DNA methylation of imprinted genes in the offspring. We find that although expression of some imprinted genes in liver of offspring is robustly and sustainably changed, methylation of the differentially methylated regions (DMRs) that control their monoallelic expression remains largely unaltered. We conclude that deregulation of imprinting through a general effect on DMR methylation is unlikely to be a common factor in developmental programming.

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Epigenetics : official journal of the DNA Methylation Society, 7, 10, 1200-10, 2012

PMID: 22968513
DOI: 10.4161/epi.22141

Open Access

Genome-wide analysis of DNA methylation in low cell numbers by reduced representation bisulfite sequencing.
Smallwood SA, Kelsey G

Development of high-throughput sequencing technologies now enables genome-wide analysis of DNA methylation of mammalian cells and tissues. Here, we present a protocol for Reduced Representation Bisulfite Sequencing (RRBS) applicable to low amounts of starting material (from 200 to 5,000 cells). RRBS is a cost-effective and powerful technique offering the advantages of absolute DNA methylation quantification and single nucleotide resolution while covering mainly CpG islands. Typically one sequencing experiment using the Illumina Genome Analyser IIx platform provides information on the DNA methylation status of more than half of the CpG islands of the mouse genome.

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Methods in molecular biology (Clifton, N.J.), 925, 1940-6029, 187-97, 2012

PMID: 22907498

Loss of XLαs (extra-large αs) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib.
E Fernández-Rebollo, A Maeda, M Reyes, S Turan, LF Fröhlich, A Plagge, G Kelsey, H Jüppner, M Bastepe

Maternal deletion of the NESP55 differentially methylated region (DMR) (delNESP55/ASdel3-4(m), delNAS(m)) from the GNAS locus in humans causes autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib(delNASm)), a disorder of proximal tubular parathyroid hormone (PTH) resistance associated with loss of maternal GNAS methylation imprints. Mice carrying a similar, maternally inherited deletion of the Nesp55 DMR (ΔNesp55(m)) replicate these Gnas epigenetic abnormalities and show evidence for PTH resistance, yet these mice demonstrate 100% mortality during the early postnatal period. We investigated whether the loss of extralarge αs (XLαs) imprinting and the resultant biallelic expression of XLαs are responsible for the early postnatal lethality in ΔNesp55(m) mice. First, we found that ΔNesp55(m) mice are hypoglycemic and have reduced stomach-to-body weight ratio. We then generated mice having the same epigenetic abnormalities as the ΔNesp55(m) mice but with normalized XLαs expression due to the paternal disruption of the exon giving rise to this Gnas product. These mice (ΔNesp55(m)/Gnasxl(m+/p-)) showed nearly 100% survival up to postnatal day 10, and a substantial number of them lived to adulthood. The hypoglycemia and reduced stomach-to-body weight ratio observed in 2-d-old ΔNesp55(m) mice were rescued in the ΔNesp55(m)/Gnasxl(m+/p-) mice. Surviving double-mutant animals had significantly reduced Gαs mRNA levels and showed hypocalcemia, hyperphosphatemia, and elevated PTH levels, thus providing a viable model of human AD-PHP-Ib. Our findings show that the hypoglycemia and early postnatal lethality caused by the maternal deletion of the Nesp55 DMR result from biallelic XLαs expression. The double-mutant mice will help elucidate the pathophysiological mechanisms underlying AD-PHP-Ib.

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Proceedings of the National Academy of Sciences of the United States of America, 109, 17, 6638-43, 2012

PMID: 22496590
DOI: 10.1073/pnas.1117608109

Open Access

Imprinted genes … and the number is?
G Kelsey, MS Bartolomei

PLoS genetics, 8, 3, e1002601, 2012

PMID: 22479197
DOI: 10.1371/journal.pgen.1002601

Open Access

De novo DNA methylation: a germ cell perspective.
SA Smallwood, G Kelsey

DNA methylation is a fundamentally important epigenetic modification of the mammalian genome that has widespread influences on gene expression. During germ-cell specification and maturation, epigenetic reprogramming occurs and the DNA methylation landscape is profoundly remodelled. Defects in this process have major consequences for embryonic development and are associated with several genetic disorders. In this review we report our current understanding of the molecular mechanisms associated with de novo DNA methylation in germ cells. We discuss recent discoveries connecting histone modifications, transcription and the DNA methylation machinery, and consider how these new findings could lead to a model for methylation establishment. Elucidating how DNA methylation marks are established in the germline has been a challenge for nearly 20 years, but represents a key step towards a full understanding of several biological processes including genomic imprinting, epigenetic reprogramming and the establishment of the pluripotent state in early embryos.

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Trends in genetics : TIG, 28, 1, 33-42, 2012

PMID: 22019337
DOI: 10.1016/j.tig.2011.09.004

A web of imprinting in stem cells.
G Kelsey

Imprinted genes are the prototypical epigenetically regulated genes. On the basis of findings in adult lung stem cells, Zacharek et al. (2011) suggest in this issue of Cell Stem Cell that epigenetic silencing of imprinted genes is a common requirement for maintaining self-renewal in adult stem cell populations.

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Cell stem cell, 9, 3, 177-8, 2011

PMID: 21885011
DOI: 10.1016/j.stem.2011.08.008

Open Access

Imprinted genes and hypothalamic function.
E Ivanova, G Kelsey

Genomic imprinting is an important and enigmatic form of gene regulation in mammals in which one copy of a gene is silenced in a manner determined by its parental history. Imprinted genes range from those with constitutive monoallelic silencing to those, typically more remote from imprinting control regions, that display developmentally regulated, tissue-specific or partial monoallelic expression. This diversity may make these genes, and the processes they control, more or less sensitive to factors that modify or disrupt epigenetic marks. Imprinted genes have important functions in development and physiology, including major endocrine/neuroendocrine axes. Owing to is central role in coordinating growth, metabolism and reproduction, as well as evidence from genetic and knockout studies, the hypothalamus may be a focus for imprinted gene action. Are there unifying principles that explain why a gene should be imprinted? Conflict between parental genomes over limiting maternal resources, but also co-adaptation between mothers and offspring, have been invoked to explain the evolution of imprinting. Recent reports suggest there may be many more genes imprinted in the hypothalamus than hitherto expected, and it will be important for these new candidates to be validated and to determine whether they conform to current notions of how imprinting is regulated. In fully evaluating the role of imprinted genes in the hypothalamus, much work needs to be done to identify the specific neuronal populations in which particular genes are expressed, establish whether there are pathways in common and whether imprinted genes are involved in long-term programming of hypothalamic functions.

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Journal of molecular endocrinology, 47, 2, R67-74, 2011

PMID: 21798993
DOI: 10.1530/JME-11-0065

Open Access

DNA methylation: a new twist in the tail.
G Kelsey

Cell research, 21, 8, 1155-6, 2011

PMID: 21727909
DOI: 10.1038/cr.2011.110

Open Access