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Anne C Ferguson-Smith

Publications and source records attributed to Anne C Ferguson-Smith.

At least 19 recordsLinked to original sources
PubMed2026

Regulatory mechanisms of maternal imprinting at the murine Dlk1-Dio3 domain.

Genomic imprinting is an epigenetic process causing parent-of-origin specific gene expression. The Dlk1-Dio3 domain is one of the largest imprinted clusters. While DNA methylation at an intergenic CpG-island (IG-CGI) within the imprinting control region (ICR) controls expression from the paternal chromosome, mechanisms regulating the unmethylated maternal chromosome remain unknown. Within the transcriptional regulatory element (IG-TRE) of the ICR, deletions identified a minimal region in vitro exhibiting both silencing and enhancing activity, with SOX2 and ZFP281 contributing to enhancer function on the maternal chromosome. In vivo, however, this deletion did not affect maternal expression in mouse embryos; instead it activated Dlk1 on both parental chromosomes. Combining deletion of this IG-TRE with the lethal IG-CGI deletion rescued lethality in mice by balancing Dlk1 expression, despite persistent maternal gene upregulation. These results demonstrate that loss of expression at this domain is more detrimental than gain, highlighting the importance of in vivo analysis. Identification of active regulatory factors on the unmethylated maternal chromosome challenges the prevailing view that imprinting is primarily a methylation-driven phenomenon, further revealing the sophisticated hierarchical mechanisms governing imprinting control.

Animals↗
PubMed2025

Dynamic allelic expression in mouse mammary glands across the adult developmental cycle.

The mammary gland, which primarily develops postnatally, undergoes significant changes during pregnancy and lactation to facilitate milk production. Through the generation and analysis of 480 transcriptomes, we provide the most detailed allelic expression map of the mammary gland, cataloguing cell-type-specific expression from ex-vivo purified cell populations over 10 developmental stages, enabling comparative analysis. The work identifies genes involved in the mammary gland cycle, parental-origin-specific and genetic background-specific expression at cellular and temporal resolution, genes associated with human lactation disorders and breast cancer. Genomic imprinting, a mechanism regulating gene expression based on parental origin, is crucial for controlling gene dosage and stem cell potential throughout development. The analysis identified 25 imprinted genes monoallelically expressed in the mammary gland, with several showing allele-specific expression in distinct cell types. No novel imprinted genes were identified and the absence of biallelically expressed imprinted genes suggests that, unlike in brain, selective absence of imprinting does not regulate gene dosage in the mammary gland. This research highlights transcriptional dynamics within mammary gland cells and identifies novel candidate genes potentially significant in the tissue during pregnancy and lactation. Overall, this comprehensive atlas represents a valuable resource for future studies on expression and transcriptional dynamics in mammary cells.

Animals↗
PubMed2006

Differential regulation of imprinting in the murine embryo and placenta by the Dlk1-Dio3 imprinting control region.

Genomic imprinting is an epigenetic mechanism controlling parental-origin-specific gene expression. Perturbing the parental origin of the distal portion of mouse chromosome 12 causes alterations in the dosage of imprinted genes resulting in embryonic lethality and developmental abnormalities of both embryo and placenta. A 1 Mb imprinted domain identified on distal chromosome 12 contains three paternally expressed protein-coding genes and multiple non-coding RNA genes, including snoRNAs and microRNAs, expressed from the maternally inherited chromosome. An intergenic, parental-origin-specific differentially methylated region, the IG-DMR, which is unmethylated on the maternally inherited chromosome, is necessary for the repression of the paternally expressed protein-coding genes and for activation of the maternally expressed non-coding RNAs: its absence causes the maternal chromosome to behave like the paternally inherited one. Here, we characterise the developmental consequences of this epigenotype switch and compare these with phenotypes associated with paternal uniparental disomy of mouse chromosome 12. The results show that the embryonic defects described for uniparental disomy embryos can be attributed to this one cluster of imprinted genes on distal chromosome 12 and that these defects alone, and not the mutant placenta, can cause prenatal lethality. In the placenta, the absence of the IG-DMR has no phenotypic consequence. Loss of repression of the protein-coding genes occurs but the non-coding RNAs are not repressed on the maternally inherited chromosome. This indicates that the mechanism of action of the IG-DMR is different in the embryo and the placenta and suggests that the epigenetic control of imprinting differs in these two lineages.

Animals↗
PubMed2006

Complementary roles of genes regulated by two paternally methylated imprinted regions on chromosomes 7 and 12 in mouse placentation.

Imprinted genes have prominent effects on placentation; however, there is limited knowledge about the manner in which the genes controlled by two paternally methylated regions on chromosomes 7 and 12 contribute to placentation. In order to clarify the functions of these genes in mouse placentation, we examined transcription levels of the paternally methylated genes, tissue differentiation and development and the circulatory system in placentae derived from three types of bi-maternal conceptuses that contained genomes of non-growing (ng) and fully grown (fg) oocytes. The genetic backgrounds of the ng oocytes were as follows: one was derived from the wild-type (ngWT) and another from mutant mice carrying a 13 kb deletion in the H19 transcription unit including the germline-derived differentially methylated region (H19-DMR) on chromosome 7 (ngDeltach7). Another set of oocytes was derived from mutant mice carrying a 4.15 kb deletion in the intergenic germline-derived DMR (IG-DMR) on chromosome 12 (ngDeltach12). Although placental mass was lower in the ngWT/fg placentae compared with that in the WT placentae, it was recovered in the ngDeltach7/fg placentae, but not in the ngDeltach12/fg placentae. The ngDeltach7/fg placental growth improvement was associated with severe dysplasia such as an expanded spongiotrophoblast layer and a malformed labyrinthine zone. In contrast, the ngDeltach12/fg placentae retained the layer structures with expanded giant cells, but their total masses were smaller with a normal circulatory system in order. Our findings demonstrate that the genes controlled by the two paternally methylated regions, H19-DMR and IG-DMR, complementarily organize placentation.

Animals↗
PubMed2005

High-resolution map and imprinting analysis of the Gtl2-Dnchc1 domain on mouse chromosome 12.

The imprinted Dlk1-Dio3 region on mouse chromosome 12 contains six imprinted genes and a number of maternally expressed snoRNAs and miRNAs. Here we present a high-resolution sequence analysis of the 1.1-Mb segment telomeric to Gtl2 in mouse and a homology comparison to the human. Ppp2r5c and Dnchc1 at the telomeric end of the analyzed sequence are biallelically expressed, suggesting that the imprinted domain does not extend beyond the paternally expressed Dio3 gene. RT-PCR experiments support the predicted presence of a maternally expressed intergenic transcript(s) encompassing Gtl2, Rian, and Mirg. These maternally expressed genes, and also the intergenic transcript(s), show pronounced expression in the adult mouse brain, whereas the paternally transcribed Dio3 and the nonimprinted Ppp2r5c and Dnchc1 are expressed in different tissues. Hence, tissue-specific coregulation of maternally expressed genes might be an important feature of this domain.

Animals↗
PubMed2005

Human embryonic stem cells as a model for studying epigenetic regulation during early development.

In order to exploit the exceptional potential of human embryonic stem cells (hESCs) in cell-replacement therapies, the genetic and epigenetic factors controlling early human development must be better defined. Limitations in human embryonic material restrict the scale of studies that can be performed, and therefore an in vitro model in which to study epigenetic regulation in human preimplantation cell types would be desirable. HESCs could provide such a model, but since they are derived from a stage in mammalian development when the genome is undergoing global epigenetic remodelling, it is unclear whether their epigenetic status would be stable or subject to variation. Herein, we discuss recent work that examines allele-specific imprinted gene expression and methylation patterns, thereby demonstrating that hESCs maintain a substantial degree of epigenetic stability during culture. Therefore, we suggest that hESCs could provide a model for studying epigenetic regulation during the early stages of human cellular pluripotency and differentiation. Furthermore, we propose specific experiments using such a model to address important questions pertaining to epigenetic mechanisms of certain human disorders.

Animals↗
PubMed2005

A small family of sushi-class retrotransposon-derived genes in mammals and their relation to genomic imprinting.

Ty3/gypsy retrotransposons are rare in mammalian genomes despite their abundance in invertebrate and other vertebrate classes. Here we identify a family of nine conserved mammalian genes with homology to Ty3/gypsy retrotransposons but which have lost their ability to autonomously retrotranspose. Of these, five map to the X chromosome while the remaining four are autosomal. Comparative phylogenetic analyses show them to have strongest homology to the sushi-ichi element from Fugu rubripes. Two of the autosomal gene members, Peg10 and Rtl1, are known to be imprinted, being expressed from the paternally inherited chromosome homologue. This suggests, consistent with the host-parasite response theory of the evolution of the imprinting mechanism, that parental-origin specific epigenetic control may be mediated by genomic "parasitic" elements such as these. Alternatively, these elements may preferentially integrate into regions that are differentially modified on the two homologous chromosomes such as imprinted domains and the X chromosome and acquire monoallelic expression. We assess the imprinting status of the remaining autosomal members of this family and show them to be biallelically expressed in embryo and placenta. Furthermore, the methylation status of Rtl1 was assayed throughout development and was found to resemble that of actively, silenced repetitive elements rather than imprinted sequences. This indicates that the ability to undergo genomic imprinting is not an inherent property of all members of this family of retroelements. Nonetheless, the conservation but functional divergence between the different members suggests that they have undergone positive selection and acquired distinct endogenous functions within their mammalian hosts.

Amino Acid Sequence↗
PubMed2005

Epigenetic status of human embryonic stem cells.

We examined the allele-specific expression of six imprinted genes and the methylation profiles of three imprinting control regions to assess the epigenetic status of human embryonic stem cells. We identified generally monoallelic gene expression and normal methylation patterns. During prolonged passage, one cell line became biallelic with respect to H19, but without loss of the gametic methylation imprint. These data argue for a substantial degree of epigenetic stability in human embryonic stem cells.

Alleles↗
PubMed2005

Imprinted X inactivation and reprogramming in the preimplantation mouse embryo.

X chromosome inactivation is a developmentally regulated process that causes one of the two X chromosomes in normal female mammals to become transcriptionally silenced, thus equalizing the expression of X-linked genes between the sexes. Such dosage compensation depends upon dynamic genetic and epigenetic events occurring very early in development. X inactivation is controlled by an X inactivation centre that is associated with the expression of non-coding RNAs required for the silencing. Also associated with the inactive X are repressive histone modifications and polycomb protein-mediated states, which are progressively acquired during the inactivation process. In mouse, two forms of X inactivation have been described. Random X inactivation happens in the derivatives of the inner cell mass (ICM) giving rise to embryos where the maternally inherited X(Xm) is inactive in some cells and the paternally derived X (Xp) is inactive in others. Random X inactivation occurs around the time of implantation. Imprinted X inactivation, the preferential inactivation of the Xp chromosome, occurs earlier and, although there has been some debate as to the precise timing of initiation of this event, is apparent in all cells early in preimplantation development, then is subsequently confined to the cells of the extraembryonic lineages. A picture is emerging whereby initial epigenetic asymmetry between the two parental X chromosomes is reprogrammed in a lineage specific manner resulting in a switch from imprinted to random inactivation in embryonic derivatives. Neither the underlying reason nor the full extent of these early lineage specific epigenetic changes is known, but they may be correlated with more genome-wide reprogramming events essential for normal development.

Alleles↗
PubMed2005

Developing essential professional skills: a framework for teaching and learning about feedback.

BACKGROUND: The ability to give and receive feedback effectively is a key skill for doctors, aids learning between all levels of the medical hierarchy, and provides a basis for reflective practice and life-long learning. How best to teach this skill? DISCUSSION: We suggest that a single "teaching the skill of feedback" session provides superficial and ineffective learning in a medical culture that often uses feedback skills poorly or discourages feedback. Our experience suggests that both the skill and the underlying attitude informing its application must be addressed, and is best done so longitudinally and reiteratively using different forms of feedback delivery. These feedback learning opportunities include written and oral, peer to peer and cross-hierarchy, public and private, thereby addressing different cognitive processes and attitudinal difficulties. SUMMARY: We conclude by asking whether it is possible to build a consensus approach to a framework for teaching and learning feedback skills?

Assertiveness↗
PubMed2005

L3mbtl, the mouse orthologue of the imprinted L3MBTL, displays a complex pattern of alternative splicing and escapes genomic imprinting.

L3mbtl encodes a member of the Polycomb group of proteins, which function as transcriptional repressors in large protein complexes. The Drosophila D-l(3)mbt protein is considered a tumor suppressor since its inactivation results in brain tumors. The human L3MBTL gene lies in a region of chromosome 20 frequently deleted in patients with myeloid malignancies and has been proposed as a candidate 20q tumor suppressor gene. Recently we have shown that L3MBTL undergoes monoallelic methylation in hematopoietic tissues and is transcribed from the paternally derived allele. The mouse L3mbtl gene is located on chromosome 2, a region of syntenic homology with human chromosome 20, and in a region containing a number of genes subject to epigenetic regulation. Here we analyze the genomic structure and alternative splicing of L3mbtl and assess its imprinting status in mouse. L3mbtl displays a complex pattern of alternative splicing involving both 5' noncoding and coding exons and is transcribed from two promoters. Unlike its human counterpart, L3mbtl escapes imprinting and there is no differential methylation of its CpG island.

Alternative Splicing↗
PubMed2004

A large imprinted microRNA gene cluster at the mouse Dlk1-Gtl2 domain.

microRNAs (or miRNAs) are small noncoding RNAs (21 to 25 nucleotides) that are processed from longer hairpin RNA precursors and are believed to be involved in a wide range of developmental and cellular processes, by either repressing translation or triggering mRNA degradation (RNA interference). By using a computer-assisted approach, we have identified 46 potential miRNA genes located in the human imprinted 14q32 domain, 40 of which are organized as a large cluster. Although some of these clustered miRNA genes appear to be encoded by a single-copy DNA sequence, most of them are arranged in tandem arrays of closely related sequences. In the mouse, this miRNA gene cluster is conserved at the homologous distal 12 region. In vivo all the miRNAs that we have detected are expressed in the developing embryo (both in the head and in the trunk) and in the placenta, whereas in the adult their expression is mainly restricted to the brain. We also show that the miRNA genes are only expressed from the maternally inherited chromosome and that their imprinted expression is regulated by an intergenic germline-derived differentially methylated region (IG-DMR) located approximately 200 kb upstream from the miRNA cluster. The functions of these miRNAs, which seem only conserved in mammals, are discussed both in terms of epigenetic control and gene regulation during development.

Animals↗
PubMed2004

Imprinting of the human L3MBTL gene, a polycomb family member located in a region of chromosome 20 deleted in human myeloid malignancies.

L3MBTL encodes a member of the Polycomb family of proteins, which, together with Trithorax group proteins, is responsible for the coordinated regulation of patterns of gene activity. Members of the Polycomb family also regulate self renewal of normal and malignant hematopoietic stem cells. L3MBTL lies in a region of chromosome 20, deletion of which is associated with myeloid malignancies and represents a good candidate for a 20q target gene. However, mutations of L3MBTL have not been identified in patients with 20q deletions or in cytogenetically normal patients. Here we demonstrate that monoallelic methylation of two CpG islands correlates with transcriptional silencing of L3MBTL, and that L3MBTL transcription occurs from the paternally derived allele in five individuals from two families. Expression of the paternally derived allele was observed in multiple hematopoietic cell types as well as in bone marrow derived mesenchymal cells. Deletions of 20q associated with myeloid malignancies resulted in loss of either the unmethylated or methylated allele. Our results demonstrate that L3MBTL represents a previously undescribed imprinted locus, a vertebrate Polycomb group gene shown to be regulated by this mechanism, and has implications for the pathogenesis of myeloid malignancies associated with 20q deletions.

Alleles↗
PubMed2004

Developmental dynamics of the definitive mouse placenta assessed by stereology.

The mouse is an excellent model for studying the genetic basis of placental development, but analyses are restricted by the lack of quantitative data describing normal murine placental structure. This study establishes a technique for generating such data, applies stereological techniques on systematic uniform random sections of placentas between E12.5-E18.5 of gestation (E1.0 = day of the vaginal plug), and considers the results in the context of development of the labyrinth zone. Half of each placenta was wax embedded and exhaustively sectioned to determine absolute volumes of the labyrinth zone (Lz), junctional zone (Jz), and decidua using the Cavalieri principle. The other half was resin embedded and 1-microm sections were used to generate all volume, surface, and length densities within the Lz. Maximum placental volume is reached by E16.5, whereas the Lz volume fraction increases until E18.5 at the expense of the Jz and decidua. Within the Lz, the absolute volume and surface area of maternal blood spaces (MBS) expand rapidly between E14.5 and E16.5, with no increase thereafter. In contrast, fetal capillary development is linear and continues for longer than that of the MBS. The interhemal membrane separating maternal and fetal circulations undergoes thinning prior to expansion of maternal and fetal surface areas, achieving a harmonic mean thickness of 4.39 microm by E18.5. The specific diffusion capacity for oxygen of the interhemal membrane is maximal by E16.5, which may be necessary to support rapid fetal growth until the end of gestation.

Animals↗