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Deborah J.g. Mackay - One of the best experts on this subject based on the ideXlab platform.
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Diabetes Mellitus, 6q24-Related Transient Neonatal
2015Co-Authors: I. K. Temple, Deborah J.g. Mackay, Louise E. DochertyAbstract:Clinical characteristics 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) is defined as transient neonatal diabetes mellitus caused by genetic aberrations of the imprinted locus at 6q24. The cardinal features are: severe intrauterine growth retardation, hyperglycemia that begins in the neonatal period in a term infant and resolves by age 18 months, dehydration, and absence of ketoacidosis. Macroglossia and umbilical hernia may be present. 6q24-TNDM associated with a multilocus imprinting disturbance (MLID) can be associated with marked hypotonia, congenital heart disease, deafness, neurologic features including epilepsy, and renal malformations. Diabetes mellitus usually starts within the first week of life and lasts on average three months but can last longer than a year. Although insulin is usually required initially, the need for insulin gradually declines over time. Intermittent episodes of hyperglycemia may occur in childhood, particularly during intercurrent illnesses. Diabetes mellitus may recur in adolescence or later in adulthood. Women who have had 6q24-TNDM are at risk for relapse during pregnancy. Diagnosis/testing The diagnosis of 6q24-TNDM is established in a proband with transient neonatal diabetes mellitus and DNA methylation analysis demonstrating relative hypomethylation within the 6q24 differentially methylated region (DMR). 6q24-TNDM is caused by overexpression of the imprinted genes at 6q24 (PLAGL1 and HYMAI). The DMR (i.e., PLAGL1 TSS alt-DMR) is present within the shared promoter of these genes. Normally, expression of the maternal alleles of PLAGL1 and HYMAI is silenced by DMR methylation and only the paternal alleles of PLAGL1 and HYMAI are expressed. Additional molecular genetic testing can establish the underlying genetic mechanism, which is required for genetic counseling. Three different genetic mechanisms resulting in twice the normal dosage of PLAGL1 and HYMAI (and thus causing 6q24-TNDM) are (1) paternal uniparental disomy of chromosome 6, (2) duplication of 6q24 on the paternal allele, and (3) hypomethylation of the maternal PLAGL1 TSS alt-DMR, resulting in inappropriate expression of the maternal PLAGL1 and HYMAI alleles. Maternal PLAGL1 TSS alt-DMR hypomethylation may result from an isolated imprinting variant or as part of MLID. Biallelic ZFP57 pathogenic variants account for almost half of TNDM-MLID. Management Treatment of manifestations: Rehydration and IV insulin are usually required at the time of diagnosis; subcutaneous insulin is introduced as soon as possible and used until blood glucose levels stabilize. Later recurrence of diabetes may require diet modifications alone, oral agents, or insulin. Prevention of secondary complications: Prompt treatment of dehydration to avoid sequelae. Surveillance: Periodic glucose tolerance tests (abnormalities suggest future recurrence); monitoring of growth and development. Agents/circumstances to avoid: Factors that predispose to late-onset diabetes or risk factors for cardiovascular disease. Evaluation of relatives at risk: Screening for diabetes mellitus in relatives who have inherited a paternal 6q24 duplication or who are at risk of having inherited two ZFP57 pathogenic variants. Genetic counseling The risk to sibs and offspring of a proband of having 6q24-TNDM or of developing diabetes later in life depends on the genetic mechanism in the family. Recurrence risk counseling by a genetics professional is strongly recommended. 6q24-TNDM caused by paternal UPD6 is typically a de novo, non-recurrent event. 6q24-TNDM caused by paternal duplication of 6q24 can occur de novo, be inherited in an autosomal dominant manner, or be inherited as part of a complex chromosome rearrangement; TNDM caused by inherited duplication of 6q24 may recur in sibs and offspring of a proband if the duplication is inherited from the father. Prenatal diagnosis of paternal duplication of 6q24 is possible in pregnancies at risk for a structural chromosome abnormality. TNDM caused by hypomethylation of the PLAGL1 TSS alt-DMR is a de novo non-recurrent event in the majority of individuals, particularly if hypomethylation is restricted to this DMR and does not affect other imprinted loci. However, TNDM as part of a multilocus imprinting disturbance (TNDM-MLID) has a significant genetic component. TNDM-MLID is inherited in an autosomal recessive manner when caused by pathogenic variants in ZFP57; however, the phenotype of homozygous or compound heterozygous sibs is variable and cannot be predicted by molecular genetic testing. Pathogenic variants in additional genes are suspected of causing TNDM-MLID but are currently unknown. Therefore, caution should be exercised when counseling the heritability of TNDM associated with imprinting disturbance at the PLAGL1 TSS alt-DMR.
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A familial disorder of altered DNA-methylation
Journal of Medical Genetics, 2014Co-Authors: Almuth Caliebe, Jasmin Beygo, Eva Jüttner, Deniz Kanber, Andrea Haake, Julia Richter, Bernhard Korn, Susanne Bens, Ole Ammerpohl, Deborah J.g. MackayAbstract:BACKGROUND: In a subset of imprinting disorders caused by epimutations, multiple imprinted loci are affected. Familial occurrence of multilocus imprinting disorders is rare. PURPOSE/OBJECTIVE: We have investigated the clinical and molecular features of a familial DNA-methylation disorder. METHODS: Tissues of affected individuals and blood samples of family members were investigated by conventional and molecular karyotyping. Sanger sequencing and RT-PCR of imprinting-associated genes (NLRP2, NLRP7, ZFP57, KHDC3L, DNMT1o), exome sequencing and locus-specific, array-based and genome-wide technologies to determine DNA-methylation were performed. RESULTS: In three offspring of a healthy couple, we observed prenatal onset of severe growth retardation and dysmorphism associated with altered DNA-methylation at paternally and maternally imprinted loci. Array-based analyses in various tissues of the offspring identified the DNA-methylation of 2.1% of the genes in the genome to be recurrently altered. Despite significant enrichment of imprinted genes (OR 9.49), altered DNA-methylation predominately (90.2%) affected genes not known to be imprinted. Sequencing of genes known to cause comparable conditions and exome sequencing in affected individuals and their ancestors did not unambiguously point to a causative gene. CONCLUSIONS: The family presented herein suggests the existence of a familial disorder of DNA-methylation affecting imprinted but also not imprinted gene loci potentially caused by a maternal effect mutation in a hitherto not identified gene.
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Clinical utility gene card for: Transient Neonatal Diabetes Mellitus, 6q24-related
European Journal of Human Genetics, 2014Co-Authors: Deborah J.g. Mackay, Guiomar Perez De Nanclares, Reiner Siebert, Susanne Bens, I. Karen TempleAbstract:aOwing to very small patient numbers, the precise percentages of different molecular aetiologies differ slightly as the sizes of patient cohorts increase. b490% of paternal uniparental disomy in 6q24 TNDM is whole-chromosome isodisomy; however, segmental UPD and heterodisomy are also seen. Maternal uniparental disomy of chromosome 6 is not associated with 6q24 TNDM. cPaternally inherited duplications of varying sizes have been identified in 6q24 TNDM, but as all contain PLAGL1, they are here designated PLAGL1 duplications. Maternally inherited duplications of PLAGL1 are not associated with 6q24 TNDM. d60% of cases with PLAGL1 hypomethylation have Multilocus Methylation Defect, that is, defects in imprinted DNA methylation at multiple imprinted loci (MLMD). Of these, approximately half have homozygous mutation of ZFP573 (a mutation database exists for ZFP57: www.lovd.nl/ ZFP57). PLAGL1 hypomethylation may also be part of MLMD associated with rare mutations in NLRP2 (NM_001174081), NLRP7 (NM_001127255) and KHDC3L (NM_001017361), but individuals affected by such syndromes may not present with 6q24 TNDM.
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Transient Neonatal Diabetes Mellitus in a Turkish Patient with Three Novel Homozygous Variants in the ZFP57 Gene
Journal of clinical research in pediatric endocrinology, 2013Co-Authors: Mehmet Boyraz, Korkut Ulucan, Necati Taskin, Teoman Akcay, Sarah E. Flanagan, Deborah J.g. MackayAbstract:Neonatal diabetes mellitus (NDM) is a rare form of diabetes that presents within the first six months of life. Nearly 70% of these cases have loss of methylation at the differentially methylated region on chromosome 6q24. To describe the findings in a Turkish male patient with NDM caused by a loss of methylation at chromosome 6q24 and three novel homozygous mutations in the ZFP57 gene, methylation-specific PCR was carried out at 6q24 and mutation analysis of ZFP57 gene was maintained by direct sequencing. Sequencing of ZFP57 gene revealed the hypomethylation of chromosome 6q24 and three novel mutations (chr6:29.641.413 A>T, 29.641.073 C>T, and 29.640.855 G>C), respectively. The latter mutation seems to display the patient's condition due to a highly conservative amino acid substitution in the protein. We suggest the ZFP57 gene as a causative factor for NDM and it should be considered in genetic testing. Further studies including functional analysis of the detected mutations will provide precise information regarding the effect of the mutations.
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Transient Neonatal Diabetes, ZFP57, and Hypomethylation of Multiple Imprinted Loci: A detailed follow-up
Diabetes care, 2012Co-Authors: Susanne E Boonen, Deborah J.g. Mackay, Johanne M D Hahnemann, Karen Grønskov, Andreas P Haemers, Louise E. Docherty, Anna Lehmann, Lise G. Larsen, Yves Kockaerts, Lutgarde DoomsAbstract:OBJECTIVE Transient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5% of the cases are due to recessive ZFP57 mutations, causing hypomethylation at the TNDM locus and other imprinted loci (HIL). This has consequences for patient care, because it has impact on the phenotype and recurrence risk for families. We have determined the genotype, phenotype, and epigenotype of the first 10 families to alert health professionals to this newly described genetic subgroup of diabetes. RESEARCH DESIGN AND METHODS The 10 families (14 homozygous/compound heterozygous individuals) with ZFP57 mutations were ascertained through TNDM1 diagnostic testing. ZFP57 was sequenced in probands and their relatives, and the methylation levels at multiple maternally and paternally imprinted loci were determined. Medical and family histories were obtained, and clinical examination was performed. RESULTS The key clinical features in probands were transient neonatal diabetes, intrauterine growth retardation, macroglossia, heart defects, and developmental delay. However, the finding of two homozygous relatives without diabetes and normal intelligence showed that the phenotype could be very variable. The epigenotype always included total loss of methylation at the TNDM1 locus and reproducible combinations of differential hypomethylation at other maternally imprinted loci, including tissue mosaicism. CONCLUSIONS There is yet no clear genotype–epigenotype–phenotype correlation to explain the variable clinical presentation, and this results in difficulties predicting the prognosis of affected individuals. However, many cases have a more severe phenotype than seen in other causes of TNDM1. Further cases and global epigenetic testing are needed to clarify this.
Anne C. Ferguson-smith - One of the best experts on this subject based on the ideXlab platform.
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Epigenetic regulation of unique genes and repetitive elements by the KRAB zinc finger protein ZFP57
2019Co-Authors: Hui Shi, Ruslan Strogantsev, Nozomi Takahashi, Anastasiya Kazachenka, Matthew C Lorincz, Myriam Hemberger, Anne C. Ferguson-smithAbstract:Abstract Background KRAB-zinc finger proteins (KZFPs) represent one of the largest families of DNA binding proteins in vertebrate genomes and appear to have evolved to silence transposable elements (TEs) including endogenous retroviruses through sequence-specific targeting of repressive chromatin states. ZFP57 is required to maintain the post-fertilization DNA methylation memory of parental-origin at genomic imprints along with ZFP445 which is specific for imprints. However, ZFP57 has multiple methylated genomic targets. Here we conduct RNA-seq and ChIP-seq analyses in normal and ZFP57 mutant mouse ES cells to understand the relative importance of ZFP57 at unique and repetitive regions of the genome. Results Over 80% of ZFP57 targets are TEs, however, ZFP57 is not essential for their repression. The remaining targets lie within unique imprinted and non-imprinted sequences. Though loss of ZFP57 influences imprinted genes as expected, the majority of unique gene targets lose H3K9me3 with little effect on DNA methylation and very few exhibiting alterations in expression. Comparison with DNA methyltransferase-deleted ES cells (TKO) identifies remarkably similar losses of H3K9me3 and changes in expression, defining regions where H3K9me3 is secondary to DNA methylation. We show that ZFP57 is the principal methylation-sensitive KZFP recruiting KAP1 and H3K9me3 in ES cells. Finally, like imprints, other unique targets of ZFP57 are enriched for germline-derived DNA methylation including oocyte-specific methylation that is resistant to post-fertilisation epigenetic reprogramming. Conclusion Our analyses suggest the evolution of a rare DNA methylation-sensitive KZFP that is not essential for repeat silencing, but whose primary function is to maintain DNA methylation and repressive histone marks at germline derived imprinting control regions.
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The origins of genomic imprinting in mammals.
Reproduction fertility and development, 2019Co-Authors: Carol A. Edwards, Nozomi Takahashi, Jennifer A. Corish, Anne C. Ferguson-smithAbstract:Genomic imprinting is a process that causes genes to be expressed according to their parental origin. Imprinting appears to have evolved gradually in two of the three mammalian subclasses, with no imprinted genes yet identified in prototheria and only six found to be imprinted in marsupials to date. By interrogating the genomes of eutherian suborders, we determine that imprinting evolved at the majority of eutherian specific genes before the eutherian radiation. Theories considering the evolution of imprinting often relate to resource allocation and recently consider maternal-offspring interactions more generally, which, in marsupials, places a greater emphasis on lactation. In eutherians, the imprint memory is retained at least in part by zinc finger protein 57 (ZFP57), a Kruppel associated box (KRAB) zinc finger protein that binds specifically to methylated imprinting control regions. Some imprints are less dependent on ZFP57invivo and it may be no coincidence that these are the imprints that are found in marsupials. Because marsupials lack ZFP57, this suggests another more ancestral protein evolved to regulate imprints in non-eutherian subclasses, and contributes to imprinting control in eutherians. Hence, understanding the mechanisms acting at imprinting control regions across mammals has the potential to provide valuable insights into our understanding of the origins and evolution of genomic imprinting.
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Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression
Genome biology, 2015Co-Authors: Ruslan Strogantsev, Hui Shi, Felix Krueger, Kazuki Yamazawa, Poppy Gould, Megan Goldman-roberts, Kirsten R Mcewen, Bowen Sun, Roger A. Pedersen, Anne C. Ferguson-smithAbstract:Background Selective maintenance of genomic epigenetic imprints during pre-implantation development is required for parental origin-specific expression of imprinted genes. The Kruppel-like zinc finger protein ZFP57 acts as a factor necessary for maintaining the DNA methylation memory at multiple imprinting control regions in early mouse embryos and embryonic stem (ES) cells. Maternal-zygotic deletion of ZFP57 in mice presents a highly penetrant phenotype with no animals surviving to birth. Additionally, several cases of human transient neonatal diabetes are associated with somatic mutations in the ZFP57 coding sequence.
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Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression
Genome Biology, 2015Co-Authors: Ruslan Strogantsev, Hui Shi, Felix Krueger, Kazuki Yamazawa, Poppy Gould, Megan Goldman-roberts, Bowen Sun, Kirsten Mcewen, Roger Pedersen, Anne C. Ferguson-smithAbstract:Background Selective maintenance of genomic epigenetic imprints during pre-implantation development is required for parental origin-specific expression of imprinted genes. The Kruppel-like zinc finger protein ZFP57 acts as a factor necessary for maintaining the DNA methylation memory at multiple imprinting control regions in early mouse embryos and embryonic stem (ES) cells. Maternal-zygotic deletion of ZFP57 in mice presents a highly penetrant phenotype with no animals surviving to birth. Additionally, several cases of human transient neonatal diabetes are associated with somatic mutations in the ZFP57 coding sequence. Results Here, we comprehensively map sequence-specific ZFP57 binding sites in an allele-specific manner using hybrid ES cell lines from reciprocal crosses between C57BL/6J and Cast/EiJ mice, assigning allele specificity to approximately two-thirds of all binding sites. While half of these are biallelic and include endogenous retrovirus (ERV) targets, the rest show monoallelic binding based either on parental origin or on genetic background of the allele. Parental-origin allele-specific binding is methylation-dependent and maps only to imprinting control differentially methylated regions (DMRs) established in the germline. We identify a novel imprinted gene, Fkbp6 , which has a critical function in mouse male germ cell development. Genetic background-specific sequence differences also influence ZFP57 binding, as genetic variation that disrupts the consensus binding motif and its methylation is often associated with monoallelic expression of neighboring genes. Conclusions The work described here uncovers further roles for ZFP57-mediated regulation of genomic imprinting and identifies a novel mechanism for genetically determined monoallelic gene expression.
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ZFP57 and the Targeted Maintenance of Postfertilization Genomic Imprints
Cold Spring Harbor symposia on quantitative biology, 2015Co-Authors: Nozomi Takahashi, Ruslan Strogantsev, Dionne Gray, Angela Noon, Celia Delahaye, William C. Skarnes, Peri Tate, Anne C. Ferguson-smithAbstract:Epigenetic modifications play an important role in modulating genome function. In mammals, inappropriate epigenetic states can cause embryonic lethality and various acquired and inherited diseases; hence, it is important to understand how such states are formed and maintained in particular genomic contexts. Genomic imprinting is a process in which epigenetic states provide a sustained memory of parental origin and cause gene expression/repression from only one of the two parental chromosomes. Genomic imprinting is therefore a valuable model to decipher the principles and processes associated with the targeting and maintenance of epigenetic states in general. Kruppel-associated box zinc finger proteins (KRAB-ZFPs) are proteins that have the potential to mediate this. ZFP57, one of the best characterized proteins in this family, has been shown to target and maintain epigenetic states at imprinting control regions after fertilization. Its role in imprinting through the use of ZFP57 mutants in mouse and the wider implications of KRAB-ZFPs for the targeted maintenance of epigenetic states are discussed here.
Andrea Riccio - One of the best experts on this subject based on the ideXlab platform.
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is ZFP57 binding to h19 igf2 ig dmr affected in silver russell syndrome
Clinical Epigenetics, 2018Co-Authors: Angela Sparago, Flavia Cerrato, Andrea RiccioAbstract:Loss of paternal methylation (LOM) of the H19/IGF2 intergenic differentially methylated region (H19/IGF2:IG-DMR) causes alteration of H19/IGF2 imprinting and Silver-Russell syndrome (SRS). Recently, internal deletions of the H19/IGF2:IG-DMR have been associated with LOM and SRS when present on the paternal chromosome. In contrast, previously described deletions, most of which cause gain of methylation (GOM) and Beckwith-Wiedemann syndrome (BWS) on maternal transmission, were consistently associated with normal methylation and phenotype if paternally inherited. The presence of several target sites (ZTSs) and three demonstrated binding regions (BRs) for the imprinting factor ZFP57 in the H19/IGF2:IG-DMR suggest the involvement of this factor in the maintenance of methylation of this locus. By comparing the extension of the H19/IGF2:IG-DMR deletions with the binding profile of ZFP57, we propose that the effect of the deletions on DNA methylation and clinical phenotype is dependent on their interference with ZFP57 binding. Indeed, deletions strongly affecting a ZFP57 BR result in LOM and SRS, while deletions preserving a significant number of ZFPs in each BR do not alter methylation and are associated with normal phenotype. The generation of transgenic mouse lines in which the endogenous H19/IGF2:IG-DMR is replaced by the human orthologous locus including the three ZFP57 BRs or their mutant versions will allow to test the role of ZFP57 binding in imprinted methylation and growth phenotype. Similarly to what is proposed for maternally inherited BWS mutations and CTCF and OCT4/SOX2 binding, we suggest that deletions of the H19/IGF2:IG-DMR result in SRS with LOM if ZFP57 binding on the paternal chromosome is affected.
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Is ZFP57 binding to H19/IGF2:IG-DMR affected in Silver-Russell syndrome?
Clinical epigenetics, 2018Co-Authors: Angela Sparago, Flavia Cerrato, Andrea RiccioAbstract:Loss of paternal methylation (LOM) of the H19/IGF2 intergenic differentially methylated region (H19/IGF2:IG-DMR) causes alteration of H19/IGF2 imprinting and Silver-Russell syndrome (SRS). Recently, internal deletions of the H19/IGF2:IG-DMR have been associated with LOM and SRS when present on the paternal chromosome. In contrast, previously described deletions, most of which cause gain of methylation (GOM) and Beckwith-Wiedemann syndrome (BWS) on maternal transmission, were consistently associated with normal methylation and phenotype if paternally inherited. The presence of several target sites (ZTSs) and three demonstrated binding regions (BRs) for the imprinting factor ZFP57 in the H19/IGF2:IG-DMR suggest the involvement of this factor in the maintenance of methylation of this locus. By comparing the extension of the H19/IGF2:IG-DMR deletions with the binding profile of ZFP57, we propose that the effect of the deletions on DNA methylation and clinical phenotype is dependent on their interference with ZFP57 binding. Indeed, deletions strongly affecting a ZFP57 BR result in LOM and SRS, while deletions preserving a significant number of ZFPs in each BR do not alter methylation and are associated with normal phenotype. The generation of transgenic mouse lines in which the endogenous H19/IGF2:IG-DMR is replaced by the human orthologous locus including the three ZFP57 BRs or their mutant versions will allow to test the role of ZFP57 binding in imprinted methylation and growth phenotype. Similarly to what is proposed for maternally inherited BWS mutations and CTCF and OCT4/SOX2 binding, we suggest that deletions of the H19/IGF2:IG-DMR result in SRS with LOM if ZFP57 binding on the paternal chromosome is affected.
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Genetic and epigenetic mutations affect the DNA binding capability of human ZFP57 in transient neonatal diabetes type 1
FEBS letters, 2013Co-Authors: Ilaria Baglivo, Sabrina Esposito, Lucia De Cesare, Angela Sparago, Zahra Anvar, Vincenzo Riso, Marco Cammisa, Roberto Fattorusso, Giovanna Grimaldi, Andrea RiccioAbstract:In the mouse, ZFP57 contains three classical Cys2His2 zinc finger domains (ZF) and recognizes the methylated TGCmetCGC target sequence using the first and the second ZFs. In this study, we demonstrate that the human ZFP57 (hZFP57) containing six Cys2His2 ZFs, binds the same methylated sequence through the third and the fourth ZFs, and identify the aminoacids critical for DNA interaction. In addition, we present evidences indicating that hZFP57 mutations and hypomethylation of the TNDM1 ICR both associated with Transient Neonatal Diabetes Mellitus type 1 result in loss of hZFP57 binding to the TNDM1 locus, likely causing PLAGL1 activation.
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In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions.
Molecular cell, 2011Co-Authors: Simon Quenneville, Ilaria Baglivo, Giovanna Grimaldi, Gaetano Verde, Andrea Corsinotti, Adamandia Kapopoulou, Johan Jakobsson, Sandra Offner, Paolo V. Pedone, Andrea RiccioAbstract:The maintenance of H3K9 and DNA methylation at imprinting control regions (ICRs) during early embryogenesis is key to the regulation of imprinted genes. Here, we reveal that ZFP57, its cofactor KAP1, and associated effectors bind selectively to the H3K9me3-bearing, DNA-methylated allele of ICRs in ES cells. KAP1 deletion induces a loss of heterochromatin marks at ICRs, whereas deleting ZFP57 or DNMTs leads to ICR DNA demethylation. Accordingly, we find that ZFP57 and KAP1 associated with DNMTs and hemimethylated DNA-binding NP95. Finally, we identify the methylated TGCCGC hexanucleotide as the motif that is recognized by ZFP57 in all ICRs and in several tens of additional loci, several of which are at least ZFP57-dependently methylated in ES cells. These results significantly advance our understanding of imprinting and suggest a general mechanism for the protection of specific loci against the wave of DNA demethylation that affects the mammalian genome during early embryogenesis.
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in embryonic stem cells ZFP57 kap1 recognize a methylated hexanucleotide to affect chromatin and dna methylation of imprinting control regions
Molecular Cell, 2011Co-Authors: Simon Quenneville, Ilaria Baglivo, Giovanna Grimaldi, Gaetano Verde, Andrea Corsinotti, Adamandia Kapopoulou, Johan Jakobsson, Sandra Offner, Paolo V. Pedone, Andrea RiccioAbstract:The maintenance of H3K9 and DNA methylation at imprinting control regions (ICRs) during early embryogenesis is key to the regulation of imprinted genes. Here, we reveal that ZFP57, its cofactor KAP1, and associated effectors bind selectively to the H3K9me3-bearing, DNA-methylated allele of ICRs in ES cells. KAP1 deletion induces a loss of heterochromatin marks at ICRs, whereas deleting ZFP57 or DNMTs leads to ICR DNA demethylation. Accordingly, we find that ZFP57 and KAP1 associated with DNMTs and hemimethylated DNA-binding NP95. Finally, we identify the methylated TGCCGC hexanucleotide as the motif that is recognized by ZFP57 in all ICRs and in several tens of additional loci, several of which are at least ZFP57-dependently methylated in ES cells. These results significantly advance our understanding of imprinting and suggest a general mechanism for the protection of specific loci against the wave of DNA demethylation that affects the mammalian genome during early embryogenesis.
I. Karen Temple - One of the best experts on this subject based on the ideXlab platform.
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Clinical utility gene card for: Transient Neonatal Diabetes Mellitus, 6q24-related
European Journal of Human Genetics, 2014Co-Authors: Deborah J.g. Mackay, Guiomar Perez De Nanclares, Reiner Siebert, Susanne Bens, I. Karen TempleAbstract:aOwing to very small patient numbers, the precise percentages of different molecular aetiologies differ slightly as the sizes of patient cohorts increase. b490% of paternal uniparental disomy in 6q24 TNDM is whole-chromosome isodisomy; however, segmental UPD and heterodisomy are also seen. Maternal uniparental disomy of chromosome 6 is not associated with 6q24 TNDM. cPaternally inherited duplications of varying sizes have been identified in 6q24 TNDM, but as all contain PLAGL1, they are here designated PLAGL1 duplications. Maternally inherited duplications of PLAGL1 are not associated with 6q24 TNDM. d60% of cases with PLAGL1 hypomethylation have Multilocus Methylation Defect, that is, defects in imprinted DNA methylation at multiple imprinted loci (MLMD). Of these, approximately half have homozygous mutation of ZFP573 (a mutation database exists for ZFP57: www.lovd.nl/ ZFP57). PLAGL1 hypomethylation may also be part of MLMD associated with rare mutations in NLRP2 (NM_001174081), NLRP7 (NM_001127255) and KHDC3L (NM_001017361), but individuals affected by such syndromes may not present with 6q24 TNDM.
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6q24 transient neonatal diabetes
Reviews in Endocrine and Metabolic Disorders, 2010Co-Authors: I. Karen Temple, Julian P. H. ShieldAbstract:Transient Neonatal Diabetes (type 1) is the commonest cause of diabetes presenting in the first week of life. The majority of infants recover by 3 months of age but are predisposed to developing type 2 diabetes in later life. It is associated with low birth weight but rapid catch up by 1 year of life. The condition is usually due to genetic or epigenetic aberrations at an imprinted locus on chromosome 6q24 and can be sporadic or inherited. Early diagnosis alters medical treatment strategies and differentiates it from other types of early onset diabetes. In some individuals, diabetes may be the initial presentation of a more complex imprinting disorder due to recessive mutations in the gene ZFP57 and may be associated with other developmental problems.
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Transient neonatal diabetes mellitus type 1
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2010Co-Authors: Deborah J.g. Mackay, I. Karen TempleAbstract:Transient neonatal diabetes mellitus type 1 (TNDM1) is a rare but remarkable form of diabetes which presents in infancy, resolves in the first months of life, but then frequently recurs in later life. It is caused by overexpression of the imprinted genes PLAGL1 and HYMAI on human chromosome 6q24. The expression of these genes is normally restricted to the paternal allele as a result of maternal DNA methylation. TNDM1 is not associated with mutation of PLAGL1 or HYMAI, but rather with their overexpression via uniparental disomy, chromosome duplication, or relaxation of imprinting. Study of patients with TNDM1 has provided valuable insights into the causes of imprinting disorders. Over half of patients with maternal hypomethylation at the TNDM1 locus have additional hypomethylation of other maternally methylated imprinted genes throughout the genome, and the majority of these patients have mutations in the transcription factor ZFP57. TNDM1 with maternal hypomethylation has also been observed in patients conceived by assisted reproduction, and in discordant monozygotic twins. The variable clinical features of TNDM1 may be associated with variation in the nature of the underlying epigenetic and genetic mutations, and future study of this disorder is likely to yield further insights not only into the biological mechanisms of imprinting, but also into the contribution of epigenetics to diabetes.
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DNA hypomethylation, transient neonatal diabetes, and prune belly sequence in one of two identical twins.
European journal of pediatrics, 2009Co-Authors: Lene B Laborie, Deborah J.g. Mackay, I. Karen Temple, Anders Molven, Oddmund Søvik, Pål R. NjølstadAbstract:One known genetic mechanism for transient neonatal diabetes is loss of methylation at 6q24. The etiology of prune belly sequence is unknown but a genetic defect, affecting the mesoderm from which the triad abdominal muscle hypoplasia, urinary tract abnormalities, and cryptorchidism develop, has been suggested. We investigated a family, including one twin, with transient neonatal diabetes and prune belly sequence. Autoantibody tests excluded type 1 diabetes. Microsatellite marker analysis confirmed the twins being monozygotic. We identified no mutations in ZFP57, KCNJ11, ABCC8, GCK, HNF1A, HNF1B, HNF3B, IPF1, PAX4, or ZIC3. The proband had loss of methylation at the 6q24 locus TNDM and also at the loci IGF2R, DIRAS3, and PEG1, while the other family members, including the healthy monozygotic twin, had normal findings. The loss of methylation on chromosome 6q24 and elsewhere may indicate a generalized maternal hypomethylation syndrome, which accounts for both transient neonatal diabetes and prune belly sequence.
Ruslan Strogantsev - One of the best experts on this subject based on the ideXlab platform.
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ZFP57 regulation of transposable elements and gene expression within and beyond imprinted domains
Epigenetics & Chromatin, 2019Co-Authors: Ruslan Strogantsev, Nozomi Takahashi, Anastasiya Kazachenka, Matthew C Lorincz, Myriam Hemberger, Anne C FergusonsmithAbstract:KRAB zinc finger proteins (KZFPs) represent one of the largest families of DNA-binding proteins in vertebrate genomes and appear to have evolved to silence transposable elements (TEs) including endogenous retroviruses through sequence-specific targeting of repressive chromatin states. ZFP57 is required to maintain the post-fertilization DNA methylation memory of parental origin at genomic imprints. Here we conduct RNA-seq and ChIP-seq analyses in normal and ZFP57 mutant mouse ES cells to understand the relative importance of ZFP57 at imprints, unique and repetitive regions of the genome. Over 80% of ZFP57 targets are TEs, however, ZFP57 is not essential for their repression. The remaining targets lie within unique imprinted and non-imprinted sequences. Though the loss of ZFP57 influences imprinted genes as expected, the majority of unique gene targets lose H3K9me3 with little effect on DNA methylation and very few exhibit alterations in expression. Comparison of ZFP57 mutants with DNA methyltransferase-deleted ES cells (TKO) identifies a remarkably similar pattern of H3K9me3 loss across the genome. These data define regions where H3K9me3 is secondary to DNA methylation and we propose that ZFP57 is the principal if not sole methylation-sensitive KZFP in mouse ES cells. Finally, we examine dynamics of DNA and H3K9 methylation during pre-implantation development and show that sites bound by ZFP57 in ES cells maintain DNA methylation and H3K9me3 at imprints and at non-imprinted regions on the maternally inherited chromosome throughout preimplantation development. Our analyses suggest the evolution of a rare DNA methylation-sensitive KZFP that is not essential for repeat silencing, but whose primary function is to maintain DNA methylation and repressive histone marks at germline-derived imprinting control regions.
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Epigenetic regulation of unique genes and repetitive elements by the KRAB zinc finger protein ZFP57
2019Co-Authors: Hui Shi, Ruslan Strogantsev, Nozomi Takahashi, Anastasiya Kazachenka, Matthew C Lorincz, Myriam Hemberger, Anne C. Ferguson-smithAbstract:Abstract Background KRAB-zinc finger proteins (KZFPs) represent one of the largest families of DNA binding proteins in vertebrate genomes and appear to have evolved to silence transposable elements (TEs) including endogenous retroviruses through sequence-specific targeting of repressive chromatin states. ZFP57 is required to maintain the post-fertilization DNA methylation memory of parental-origin at genomic imprints along with ZFP445 which is specific for imprints. However, ZFP57 has multiple methylated genomic targets. Here we conduct RNA-seq and ChIP-seq analyses in normal and ZFP57 mutant mouse ES cells to understand the relative importance of ZFP57 at unique and repetitive regions of the genome. Results Over 80% of ZFP57 targets are TEs, however, ZFP57 is not essential for their repression. The remaining targets lie within unique imprinted and non-imprinted sequences. Though loss of ZFP57 influences imprinted genes as expected, the majority of unique gene targets lose H3K9me3 with little effect on DNA methylation and very few exhibiting alterations in expression. Comparison with DNA methyltransferase-deleted ES cells (TKO) identifies remarkably similar losses of H3K9me3 and changes in expression, defining regions where H3K9me3 is secondary to DNA methylation. We show that ZFP57 is the principal methylation-sensitive KZFP recruiting KAP1 and H3K9me3 in ES cells. Finally, like imprints, other unique targets of ZFP57 are enriched for germline-derived DNA methylation including oocyte-specific methylation that is resistant to post-fertilisation epigenetic reprogramming. Conclusion Our analyses suggest the evolution of a rare DNA methylation-sensitive KZFP that is not essential for repeat silencing, but whose primary function is to maintain DNA methylation and repressive histone marks at germline derived imprinting control regions.
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Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression
Genome biology, 2015Co-Authors: Ruslan Strogantsev, Hui Shi, Felix Krueger, Kazuki Yamazawa, Poppy Gould, Megan Goldman-roberts, Kirsten R Mcewen, Bowen Sun, Roger A. Pedersen, Anne C. Ferguson-smithAbstract:Background Selective maintenance of genomic epigenetic imprints during pre-implantation development is required for parental origin-specific expression of imprinted genes. The Kruppel-like zinc finger protein ZFP57 acts as a factor necessary for maintaining the DNA methylation memory at multiple imprinting control regions in early mouse embryos and embryonic stem (ES) cells. Maternal-zygotic deletion of ZFP57 in mice presents a highly penetrant phenotype with no animals surviving to birth. Additionally, several cases of human transient neonatal diabetes are associated with somatic mutations in the ZFP57 coding sequence.
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Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression
Genome Biology, 2015Co-Authors: Ruslan Strogantsev, Hui Shi, Felix Krueger, Kazuki Yamazawa, Poppy Gould, Megan Goldman-roberts, Bowen Sun, Kirsten Mcewen, Roger Pedersen, Anne C. Ferguson-smithAbstract:Background Selective maintenance of genomic epigenetic imprints during pre-implantation development is required for parental origin-specific expression of imprinted genes. The Kruppel-like zinc finger protein ZFP57 acts as a factor necessary for maintaining the DNA methylation memory at multiple imprinting control regions in early mouse embryos and embryonic stem (ES) cells. Maternal-zygotic deletion of ZFP57 in mice presents a highly penetrant phenotype with no animals surviving to birth. Additionally, several cases of human transient neonatal diabetes are associated with somatic mutations in the ZFP57 coding sequence. Results Here, we comprehensively map sequence-specific ZFP57 binding sites in an allele-specific manner using hybrid ES cell lines from reciprocal crosses between C57BL/6J and Cast/EiJ mice, assigning allele specificity to approximately two-thirds of all binding sites. While half of these are biallelic and include endogenous retrovirus (ERV) targets, the rest show monoallelic binding based either on parental origin or on genetic background of the allele. Parental-origin allele-specific binding is methylation-dependent and maps only to imprinting control differentially methylated regions (DMRs) established in the germline. We identify a novel imprinted gene, Fkbp6 , which has a critical function in mouse male germ cell development. Genetic background-specific sequence differences also influence ZFP57 binding, as genetic variation that disrupts the consensus binding motif and its methylation is often associated with monoallelic expression of neighboring genes. Conclusions The work described here uncovers further roles for ZFP57-mediated regulation of genomic imprinting and identifies a novel mechanism for genetically determined monoallelic gene expression.
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ZFP57 and the Targeted Maintenance of Postfertilization Genomic Imprints
Cold Spring Harbor symposia on quantitative biology, 2015Co-Authors: Nozomi Takahashi, Ruslan Strogantsev, Dionne Gray, Angela Noon, Celia Delahaye, William C. Skarnes, Peri Tate, Anne C. Ferguson-smithAbstract:Epigenetic modifications play an important role in modulating genome function. In mammals, inappropriate epigenetic states can cause embryonic lethality and various acquired and inherited diseases; hence, it is important to understand how such states are formed and maintained in particular genomic contexts. Genomic imprinting is a process in which epigenetic states provide a sustained memory of parental origin and cause gene expression/repression from only one of the two parental chromosomes. Genomic imprinting is therefore a valuable model to decipher the principles and processes associated with the targeting and maintenance of epigenetic states in general. Kruppel-associated box zinc finger proteins (KRAB-ZFPs) are proteins that have the potential to mediate this. ZFP57, one of the best characterized proteins in this family, has been shown to target and maintain epigenetic states at imprinting control regions after fertilization. Its role in imprinting through the use of ZFP57 mutants in mouse and the wider implications of KRAB-ZFPs for the targeted maintenance of epigenetic states are discussed here.
