scholarly journals Defective folate metabolism causes germline epigenetic instability and distinguishes Hira as a phenotype inheritance biomarker

2020 ◽  
Author(s):  
Georgina E.T. Blake ◽  
Xiaohui Zhao ◽  
Hong wa Yung ◽  
Graham J. Burton ◽  
Anne C. Ferguson-Smith ◽  
...  
Keyword(s):  
Congenital Malformations ◽  
Epigenetic Inheritance ◽  
Folate Metabolism ◽  
Transgenerational Epigenetic Inheritance ◽  
Hypomorphic Mutation ◽  
Genome Wide ◽  
A Genome ◽  
Epigenetic Instability ◽  
Transcriptional Memory ◽  
Methylation Defects

ABSTRACTThe mechanism behind transgenerational epigenetic inheritance (TEI) is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by the Mtrrgt hypomorphic mutation results in TEI of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. In this work, we use a genome-wide approach to reveal genetic stability in the Mtrrgt model and epigenome-wide differential DNA methylation in the germline of Mtrr+/gt maternal grandfathers. While epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional memory of germline methylation defects. One region encompasses the Hira gene, which is misexpressed in embryos at least until the F3 generation in a manner that distinguishes Hira transcript expression as a biomarker of maternal phenotypic inheritance.

scholarly journals Defective folate metabolism causes germline epigenetic instability and distinguishes Hira as a phenotype inheritance biomarker

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Georgina E. T. Blake ◽  
Xiaohui Zhao ◽  
Hong wa Yung ◽  
Graham J. Burton ◽  
Anne C. Ferguson-Smith ◽  
...  
Keyword(s):  
Congenital Malformations ◽  
Epigenetic Inheritance ◽  
Folate Metabolism ◽  
Transcript Expression ◽  
Transgenerational Epigenetic Inheritance ◽  
Hypomorphic Mutation ◽  
Genome Wide ◽  
Epigenetic Instability ◽  
Transcriptional Changes ◽  
Methylation Defects

AbstractThe mechanism behind transgenerational epigenetic inheritance is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by the Mtrr hypomorphic mutation results in transgenerational epigenetic inheritance of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. Here, we use genome-wide approaches to reveal genetic stability in the Mtrr model and genome-wide differential DNA methylation in the germline of Mtrr mutant maternal grandfathers. We observe that, while epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional changes that correlate with germline methylation defects. One region encompasses the Hira gene, which is misexpressed in embryos for at least three wildtype generations in a manner that distinguishes Hira transcript expression as a biomarker of maternal phenotypic inheritance.

scholarly journals A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Hannah Demond ◽  
Zahra Anvar ◽  
Bahia Namavar Jahromi ◽  
Angela Sparago ◽  
Ankit Verma ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Hydatidiform Mole ◽  
Human Oocyte ◽  
Imprinted Genes ◽  
High Coverage ◽  
Genome Wide ◽  
A Genome ◽  
Mechanistic Basis ◽  
Methylation Defects

Abstract Background Maternal effect mutations in the components of the subcortical maternal complex (SCMC) of the human oocyte can cause early embryonic failure, gestational abnormalities and recurrent pregnancy loss. Enigmatically, they are also associated with DNA methylation abnormalities at imprinted genes in conceptuses: in the devastating gestational abnormality biparental complete hydatidiform mole (BiCHM) or in multi-locus imprinting disease (MLID). However, the developmental timing, genomic extent and mechanistic basis of these imprinting defects are unknown. The rarity of these disorders and the possibility that methylation defects originate in oocytes have made these questions very challenging to address. Methods Single-cell bisulphite sequencing (scBS-seq) was used to assess methylation in oocytes from a patient with BiCHM identified to be homozygous for an inactivating mutation in the human SCMC component KHDC3L. Genome-wide methylation analysis of a preimplantation embryo and molar tissue from the same patient was also performed. Results High-coverage scBS-seq libraries were obtained from five KHDC3Lc.1A>G oocytes, which revealed a genome-wide deficit of DNA methylation compared with normal human oocytes. Importantly, germline differentially methylated regions (gDMRs) of imprinted genes were affected similarly to other sequence features that normally become methylated in oocytes, indicating no selectivity towards imprinted genes. A range of methylation losses was observed across genomic features, including gDMRs, indicating variable sensitivity to defects in the SCMC. Genome-wide analysis of a pre-implantation embryo and molar tissue from the same patient showed that following fertilisation methylation defects at imprinted genes persist, while most non-imprinted regions of the genome recover near-normal methylation post-implantation. Conclusions We show for the first time that the integrity of the SCMC is essential for de novo methylation in the female germline. These findings have important implications for understanding the role of the SCMC in DNA methylation and for the origin of imprinting defects, for counselling affected families, and will help inform future therapeutic approaches.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

Establishment of a genome-wide RNAi screen; Identification of novel genes involved in clonal maintenance of ALL

2014 ◽  
Vol 226 (03) ◽  
Author(s):  
F Ponthan ◽  
D Pal ◽  
J Vormoor ◽  
O Heidenreich
Keyword(s):  
Rnai Screen ◽  
Novel Genes ◽  
Genome Wide ◽  
A Genome

A genome-wide linkage scan for familial partial lipodystrophy susceptibility genes in a German kindreds

2007 ◽  
Vol 30 (4) ◽  
pp. 86
Author(s):  
M. Lanktree ◽  
J. Robinson ◽  
J. Creider ◽  
H. Cao ◽  
D. Carter ◽  
...  
Keyword(s):  
Subcutaneous Fat ◽  
Visceral Obesity ◽  
Fat Distribution ◽  
Dominant Negative ◽  
Molecular Forms ◽  
Partial Lipodystrophy ◽  
Genome Wide ◽  
A Genome ◽  
Familial Partial Lipodystrophy ◽  
Promoter Mutations

Background: In Dunnigan-type familial partial lipodystrophy (FPLD) patients are born with normal fat distribution, but subcutaneous fat from extremities and gluteal regions are lost during puberty. The abnormal fat distribution leads to the development of metabolic syndrome (MetS), a cluster of phenotypes including hyperglycemia, dyslipidemia, hypertension, and visceral obesity. The study of FPLD as a monogenic model of MetS may uncover genetic risk factors of the common MetS which affects ~30% of adult North Americans. Two molecular forms of FPLD have been identified including FPLD2, resulting from heterozygous mutations in the LMNA gene, and FPLD3, resulting from both heterozygous dominant negative and haploinsufficiency mutations in the PPARG gene. However, many patients with clinically diagnosed FPLD have no mutation in either LMNA or PPARG, suggesting the involvement of additional genes in FPLD etiology. Methods: Here, we report the results of an Affymetrix 10K GeneChip microarray genome-wide linkage analysis study of a German kindred displaying the FPLD phenotype and no known lipodystrophy-causing mutations. Results: The investigation identified three chromosomal loci, namely 1q, 3p, and 9q, with non-parametric logarithm of odds (NPL) scores >2.7. While not meeting the criteria for genome-wide significance, it is interesting to note that the 1q and 3p peaks contain the LMNA and PPARG genes respectively. Conclusions: Three possible conclusions can be drawn from these results: 1) the peaks identified are spurious findings, 2) additional genes physically close to LMNA, PPARG, or within 9q, are involved in FPLD etiology, or 3) alternative disease causing mechanisms not identified by standard exon sequencing approaches, such as promoter mutations, alternative splicing, or epigenetics, are also responsible for FPLD.

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