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Genomic imprinting is observed in endosperm, a placenta-like seed tissue, where transposable elements (TEs) and repeat-derived small RNAs (sRNAs) mediate epigenetic changes in plants. In imprinting, uniparental gene expression arises due to parent-specific epigenetic marks on one allele but not on the other. The importance of sRNAs and their regulation in endosperm development or in imprinting is poorly understood in crops. Here we show that a previously uncharacterized CLASSY (CLSY)-family chromatin remodeler named OsCLSY3 is essential for rice endosperm development and imprinting, acting as an upstream player in the sRNA pathway. Comparative transcriptome and genetic analysis indicated its endosperm-preferred expression and its likely paternal imprinted nature. These important features are modulated by RNA-directed DNA methylation (RdDM) of tandemly arranged TEs in its promoter. Upon perturbation of OsCLSY3 in transgenic lines, we observe defects in endosperm development and a loss of around 70% of all sRNAs. Interestingly, well-conserved endosperm-specific sRNAs (siren) that are vital for reproductive fitness in angiosperms are also dependent on OsCLSY3. We observed that many imprinted genes and seed development-associated genes are under the control of OsCLSY3. These results support an essential role of OsCLSY3 in rice endosperm development and imprinting, and propose similar regulatory strategies involving CLSY3 homologs among other cereals. Using a well-resolved spatial transcriptomics coupled with genetic data, this study identified rice CLSY3 chromatin remodeler as an upstream player in endosperm development. OsCLSY3 is imprinted and endosperm-specific, and, curiously, its expression is controlled by RdDM. [ABSTRACT FROM AUTHOR]

In mammals, imprinted genes are characterised by a monoallelic expression, which is based on parental origin and is essential for both foetal and placental development. The ZFAT gene encodes a transcriptional factor, and its non‐coding antisense RNA, ZFAT‐AS1, overlaps with the ZFAT locus. Both ZFAT and ZFAT‐AS1 are maternally imprinted in human placentas. In bovines, the imprinting status of the ZFAT and ZFAT‐AS1 genes has yet to be reported. In this study, we analysed the allelic expression of three transcript variants (X1–X3) of the bovine ZFAT and ZFAT‐AS1 genes in somatic tissues and placentas using a single nucleotide polymorphism‐based method. The results showed that bovine ZFAT exhibited isoform‐specific paternal expression. The ZFAT X2 variant exhibited monoallelic expression in the bovine placentas and biallelic expression in the six bovine somatic tissues (heart, liver, spleen, lung, kidney and brain). However, the ZFAT X1 and X3 variants were biallelically expressed in both bovine tissues and placentas. A 311 bp bovine ZFAT‐AS1 complementary DNA (cDNA) sequence was obtained by aligning the human ZFAT‐AS1 cDNA sequence with the bovine genome and conducting reverse transcription polymerase chain reaction amplification. Bovine ZFAT‐AS1 have monoallelic expression in bovine placentas and somatic tissues. In addition, the DNA methylation of two regions was characterised, including the partial promoter, and exon 1 and intron 1 regions of ZFAT, and there were no differentially methylated regions. [ABSTRACT FROM AUTHOR]

LMNA-related dilated cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure or sudden death. The condition is caused by mutation in the Lamin A/C (LMNA) gene encoding Type-A nuclear lamin proteins involved in nuclear integrity, epigenetic regulation of gene expression, and differentiation. The molecular mechanisms of the disease are not completely understood, and there are no definitive treatments to reverse progression or prevent mortality. We investigated possible mechanisms of LMNA-related DCM using induced pluripotent stem cells derived from a family with a heterozygous LMNA c.357-2A>G splice-site mutation. We differentiated one LMNA-mutant iPSC line derived from an affected female (Patient) and two non-mutant iPSC lines derived from her unaffected sister (Control) and conducted single-cell RNA sequencing for 12 samples (four from Patients and eight from Controls) across seven time points: Day 0, 2, 4, 9, 16, 19, and 30. Our bioinformatics workflow identified 125,554 cells in raw data and 110,521 (88%) high-quality cells in sequentially processed data. Unsupervised clustering, cell annotation, and trajectory inference found complex heterogeneity: ten main cell types; many possible subtypes; and lineage bifurcation for cardiac progenitors to cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Data integration and comparative analyses of Patient and Control cells found cell type and lineage-specific differentially expressed genes (DEGs) with enrichment, supporting pathway dysregulation. Top DEGs and enriched pathways included 10 ZNF genes and RNA polymerase II transcription in pluripotent cells (PP); BMP4 and TGF Beta/BMP signaling, sarcomere gene subsets and cardiogenesis, CDH2 and EMT in CMs; LMNA and epigenetic regulation, as well as DDIT4 and mTORC1 signaling in EPDCs. Top DEGs also included XIST and other X-linked genes, six imprinted genes (SNRPN, PWAR6, NDN, PEG10, MEG3, MEG8), and enriched gene sets related to metabolism, proliferation, and homeostasis. We confirmed Lamin A/C haploinsufficiency by allelic expression and Western blot. Our complex Patient-derived iPSC model for Lamin A/C haploinsufficiency in PP, CM, and EPDC provided support for dysregulation of genes and pathways, many previously associated with Lamin A/C defects, such as epigenetic gene expression, signaling, and differentiation. Our findings support disruption of epigenomic developmental programs, as proposed in other LMNA disease models. We recognized other factors influencing epigenetics and differentiation; thus, our approach needs improvement to further investigate this mechanism in an iPSC-derived model. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NB) is a complex disease, and the current understanding of NB biology is limited. Deregulation in genomic imprinting is a common event in malignancy. Since imprinted genes play crucial roles in early fetal growth and development, their role in NB pathogenesis could be suggested. Methods: We examined alterations in DNA methylation patterns of 369 NB tumours at 49 imprinted differentially methylated regions (DMRs) and assessed its association with overall survival probabilities and selected clinical and genomic features of the tumours. In addition, an integrated analysis of DNA methylation and allele-specific copy number alterations (CNAs) was performed, to understand the correlation between the two molecular events. Results: Several imprinted regions with aberrant methylation patterns in NB were identified. Regions that underwent loss of methylation in > 30% of NB samples were DMRs annotated to the genes NDN, SNRPN, IGF2, MAGEL2 and HTR5A and regions with gain of methylation were NNAT, RB1 and GPR1. Methylation alterations at six of the 49 imprinted DMRs were statistically significantly associated with reduced overall survival: MIR886, RB1, NNAT/BLCAP, MAGEL2, MKRN3 and INPP5F. RB1, NNAT/BLCAP and MKRN3 were further able to stratify low-risk NB tumours i.e. tumours that lacked MYCN amplification and 11q deletion into risk groups. Methylation alterations at NNAT/BLCAP, MAGEL2 and MIR886 predicted risk independently of MYCN amplification or 11q deletion and age at diagnosis. Investigation of the allele-specific CNAs demonstrated that the imprinted regions that displayed most alterations in NB tumours harbor true epigenetic changes and are not result of the underlying CNAs. Conclusions: Aberrant methylation in imprinted regions is frequently occurring in NB tumours and several of these regions have independent prognostic value. Thus, these could serve as potentially important clinical epigenetic markers to identify individuals with adverse prognosis. Incorporation of methylation status of these regions together with the established risk predictors may further refine the prognostication of NB patients. [ABSTRACT FROM AUTHOR]

Genomic imprinting refers to the epigenetic silencing of one of both alleles in a parent-of-origin-specific manner, particularly in genes regulating growth and development. Impaired genomic imprinting leading to the activation of the silenced allele, also called canonical loss-of-imprinting (LOI), is considered an early factor in oncogenesis. As LOI studies in clear cell renal cell carcinoma (ccRCC) are limited to IGF2, we performed a genome-wide analysis in 128 kidney normal solid tissue and 240 stage 1 ccRCC samples (TCGA RNA-seq data) to screen for canonical LOI in early oncogenesis. In ccRCC, we observed LOI (adj. p = 2.74 × 10−3) of HM13 (Histocompatibility Minor 13), a signal peptide peptidase involved in epitope generation. HM13 LOI samples featured HM13 overexpression, both compared to normal solid tissues (p = 3.00 × 10−7) and non-LOI (p = 1.27 × 10−2) samples. Upon adjustment for age and sex, HM13 expression was significantly associated with poor survival (p = 7.10 × 10−5). Moreover, HM13 overexpression consistently exacerbated with increasing tumor stage (p = 2.90 × 10−8). For IGF2, LOI was observed in normal solid tissues, but the prevalence did not increase in cancer. In conclusion, HM13 LOI is an early event in ccRCC, causing overexpression leading to poor prognosis. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B virus (HBV) infection poses a substantial threat to human health, impacting not only infected individuals but also potentially exerting adverse effects on the health of their offspring. The underlying mechanisms driving this phenomenon remain elusive. This study aims to shed light on this issue by examining alterations in paternally imprinted genes within sperm. Methods: A cohort of 35 individuals with normal semen analysis, comprising 17 hepatitis B surface antigen (HBsAg)-positive and 18 negative individuals, was recruited. Based on the previous research and the Online Mendelian Inheritance in Man database (OMIM, https://www.omim.org/), targeted promoter methylation sequencing was employed to investigate 28 paternally imprinted genes associated with various diseases. Results: Bioinformatic analyses revealed 42 differentially methylated sites across 29 CpG islands within 19 genes and four differentially methylated CpG islands within four genes. At the gene level, an increase in methylation of DNMT1 and a decrease in methylation of CUL7, PRKAG2, and TP53 were observed. DNA methylation haplotype analysis identified 51 differentially methylated haplotypes within 36 CpG islands across 22 genes. Conclusions: This is the first study to explore the effects of HBV infection on sperm DNA methylation and the potential underlying mechanisms of intergenerational influence of paternal HBV infection. [ABSTRACT FROM AUTHOR]

Summary: Adzuki bean (Vigna angularis) is an important legume crop cultivated in over 30 countries worldwide. We developed a high‐quality chromosome‐level reference genome of adzuki bean cultivar Jingnong6 by combining PacBio Sequel long‐read sequencing with short‐read and Hi‐C technologies. The assembled genome covers 97.8% of the adzuki bean genome with a contig N50 of approximately 16 Mb and a total of 32 738 protein‐coding genes. We also generated a comprehensive genome variation map of adzuki bean by whole‐genome resequencing (WGRS) of 322 diverse adzuki beans accessions including both wild and cultivated. Furthermore, we have conducted comparative genomics and a genome‐wide association study (GWAS) on key agricultural traits to investigate the evolution and domestication. GWAS identified several candidate genes, including VaCycA3;1, VaHB15, VaANR1 and VaBm, that exhibited significant associations with domestication traits. Furthermore, we conducted functional analyses on the roles of VaANR1 and VaBm in regulating seed coat colour. We provided evidence for the highest genetic diversity of wild adzuki (Vigna angularis var. nipponensis) in China with the presence of the most original wild adzuki bean, and the occurrence of domestication process facilitating transition from wild to cultigen. The present study elucidates the genetic basis of adzuki bean domestication traits and provides crucial genomic resources to support future breeding efforts in adzuki bean. [ABSTRACT FROM AUTHOR]

Background: Differentially methylated imprint control regions (ICRs) regulate the monoallelic expression of imprinted genes. Their epigenetic dysregulation by environmental exposures throughout life results in the formation of common chronic diseases. Unfortunately, existing Infinium methylation arrays lack the ability to profile these regions adequately. Whole genome bisulfite sequencing (WGBS) is the unique method able to profile the ICRs. However, it is very expensive and it requires not only a high coverage, but it is also computationally intensive to assess these regions. Findings: To address this deficiency, we developed a custom methylation array containing 22,819 probes. Among them, 10,438 are CG probes targeting unique CpG sites, with 9,757 probes successfully mapping to 1,088 out of the 1,488 candidate ICRs recently described. To assess the performance of the array, we created matched samples processed with the Human Imprintome array and WGBS, which is the current standard method for assessing the methylation of the Human Imprintome. We compared the methylation levels from the shared CpG sites, and obtained a mean R2 = 0.569. We also created matched samples processed with the Human Imprintome array and the Infinium Methylation EPIC v2 array, and obtained a mean R2 = 0.796. Furthermore, replication experiments demonstrated high reliability (ICC: 0.799–0.945). Conclusions: Our custom array will be useful for replicable and accurate assessment, mechanistic insight, and targeted investigation of ICRs. This tool should accelerate the discovery of ICRs associated with a wide range of diseases and exposures, and advance our understanding of genomic imprinting and its relevance in development and disease formation throughout the life course. [ABSTRACT FROM AUTHOR]

The discovery of Allele-Specific Methylation (ASM) is an important research field in biology as it regulates genomic imprinting, which has been identified as the cause of some genetic diseases. Nevertheless, the high computational cost of the bioinformatic tools developed for this purpose prevents their application to large-scale datasets. Hence, much faster tools are required to further progress in this research field. In this work we present PARamrfinder, a parallel tool that applies a statistical model to identify ASM in data from high-throughput short-read bisulfite sequencing. It is based on the state-of-the-art sequential tool amrfinder, which is able to detect ASM at regional level from Bisulfite Sequencing (BS-Seq) experiments in the absence of Single Nucleotide Polymorphism information. PARamrfinder provides the same Allelically Methylated Regions as amrfinder but at significantly reduced runtime thanks to exploiting the compute capabilities of common multicore CPU clusters and MPI RMA operations to attain an efficient dynamic workload balance. As an example, our tool is up to 567 times faster for real data experiments on a cluster with 8 nodes, each one containing two 16-core processors. The source code of PARamrfinder, as well as a reference manual, is available at https://github.com/UDC-GAC/PARamrfinder. [ABSTRACT FROM AUTHOR]

Seed dispersal affects gene flow and hence genetic differentiation of plant populations. During the Late Quaternary, most fruit‐eating and seed‐dispersing megafauna went extinct, but whether these animals have left signatures in the population genetics of their food plants, particularly those with large, 'megafaunal' fruits (i.e. >4 cm—megafruits), remains unclear.Here, we assessed the population history, genetic differentiation and recent migration among populations of four animal‐dispersed palm (Arecaceae) species with large (Borassus madagascariensis), medium‐sized (Hyphaene coriacea, Bismarckia nobilis) and small (Chrysalidocarpus madagascariensis) fruits on Madagascar. We integrated double‐digest restriction‐site‐associated DNA sequencing (ddRAD) of 167 individuals from 25 populations with (past) distribution ranges for extinct (e.g., giant lemurs and elephant birds) and extant seed‐dispersing animals, landscape and human impact data, and applied linear mixed‐effects models to explore the drivers of genetic variation in Malagasy palms.Palm populations that shared more megafrugivore species in the past had lower genetic differentiation than populations that shared fewer megafrugivore species. This suggests that megafrugivore‐mediated seed dispersal in the past may have led to frequent gene flow among populations. In comparison, extant frugivore diversity only decreased genetic differentiation in the small‐fruited palm. Furthermore, genetic differentiation of all palm species decreased with landscape connectivity (i.e. environmental suitability, forest cover and river density) and human impact (i.e. road density), while migration rates of the small‐fruit palm increased with road density.Synthesis. Our results suggest that the legacy of megafrugivores regularly achieving long dispersal distances is still reflected in the population genetics of palms that were formerly dispersed by such animals. Furthermore, low genetic differentiation was possibly maintained after the megafauna extinctions through alternative dispersal (e.g. human‐ or river‐mediated), long generation times and long lifespans of these megafruit palms. Our study illustrates how species interactions that happened >1000 years ago can leave imprints in their population genetics. [ABSTRACT FROM AUTHOR]

Hydatidiform moles, including both complete and partial moles, constitute a subset of gestational trophoblastic diseases characterized by abnormal fertilization resulting in villous hydrops and trophoblastic hyperplasia with or without embryonic development. This involves chromosomal abnormalities, where one or two sperms fertilize an empty oocyte (complete hydatidiform mole (CHM); mostly 46,XX) or two sperms fertilize one oocyte (partial hydatidiform mole (PHM); mostly 69,XXY). Notably, recurrent occurrences are associated with abnormal genomic imprinting of maternal effect genes such as NLRP7 (chromosome 19q13.4) and KHDC3L (chromosome 6q1). Ongoing efforts to enhance identification methods have led to the identification of growth-specific markers, including p57 (cyclin-dependent kinase inhibitor 1C; CDKN1C), which shows intact nuclear expression in the villous cytotrophoblast and villous stromal cells in PHMs and loss of expression in CHMs. Treatment of hydatidiform moles includes dilation and curettage for uterine evacuation of the molar pregnancy followed by surveillance of human chorionic gonadotropin (HCG) levels to confirm disease resolution and rule out the development of any gestational trophoblastic neoplasia. In this review, we provide a synopsis of the existing literature on hydatidiform moles, their diagnosis, histopathologic features, and management. [ABSTRACT FROM AUTHOR]

Background: Kurozu is a traditional Japanese rice vinegar characterized by its brown color and that has been shown to improve hypertension, hypercholesterolemia, and carbohydrate metabolism. Kurozu has also been suggested to confer health benefits by altering gene expression; however, the molecular basis is not yet understood. Objective: We previously reported that the intake of Kurozu increased the expression hepatic Sirt1 and microRNA (miR). These changes in gene expression may be attributed to histone modifications. Therefore, the current research explored the effects of supplementation with concentrated Kurozu (CK) on histone modifications in the liver. Methods: Over a period of 50 weeks, mice received a high-fat diet (HFD), HFD with CK, or a standard diet (SD). The study focused on the impact of CK on gene expression related to lipid metabolism in the liver. Results: A microarray analysis revealed that HFD increased the expression of the miR cluster located on chromosome 12, while this change was suppressed by CK. The chromatin modification region upstream of the miR cluster was analyzed using a Chip assay. HFD significantly increased the levels of dimethylation of histone H3 lysine 4 (H3K4me2) and monoacetylation of histone H3 lysine 27 (H3K27ac). HFD also increased H3K4me2 levels, and this change was inhibited by HFD with CK. MiR-127-5p and -134-5p, which are present in the miR cluster, inhibited MLXIPL, a transcription factor involved in synthesizing fatty acids from carbohydrates. Further experiments with human colon cancer cells demonstrated that miR-127-5p and -134-5p significantly knocked down MLXIPL. Conclusion: These results suggested that HFD affects miR expression levels by changing chromatin modification levels and that supplementation with CK suppressed HFD-induced increases in H3K4me2 levels. Furthermore, HFD upregulated the expression of miR-127-5p and -134-5p, which in turn suppressed MLXIPL. [ABSTRACT FROM AUTHOR]

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Abstract Background Neuroblastoma (NB) is a complex disease, and the current understanding of NB biology is limited. Deregulation in genomic imprinting is a common event in malignancy. Since imprinted genes play crucial roles in early fetal growth and development, their role in NB pathogenesis could be suggested. Methods We examined alterations in DNA methylation patterns of 369 NB tumours at 49 imprinted differentially methylated regions (DMRs) and assessed its association with overall survival probabilities and selected clinical and genomic features of the tumours. In addition, an integrated analysis of DNA methylation and allele-specific copy number alterations (CNAs) was performed, to understand the correlation between the two molecular events. Results Several imprinted regions with aberrant methylation patterns in NB were identified. Regions that underwent loss of methylation in > 30% of NB samples were DMRs annotated to the genes NDN, SNRPN, IGF2, MAGEL2 and HTR5A and regions with gain of methylation were NNAT, RB1 and GPR1. Methylation alterations at six of the 49 imprinted DMRs were statistically significantly associated with reduced overall survival: MIR886, RB1, NNAT/BLCAP, MAGEL2, MKRN3 and INPP5F. RB1, NNAT/BLCAP and MKRN3 were further able to stratify low-risk NB tumours i.e. tumours that lacked MYCN amplification and 11q deletion into risk groups. Methylation alterations at NNAT/BLCAP, MAGEL2 and MIR886 predicted risk independently of MYCN amplification or 11q deletion and age at diagnosis. Investigation of the allele-specific CNAs demonstrated that the imprinted regions that displayed most alterations in NB tumours harbor true epigenetic changes and are not result of the underlying CNAs. Conclusions Aberrant methylation in imprinted regions is frequently occurring in NB tumours and several of these regions have independent prognostic value. Thus, these could serve as potentially important clinical epigenetic markers to identify individuals with adverse prognosis. Incorporation of methylation status of these regions together with the established risk predictors may further refine the prognostication of NB patients.

Abstract Background Differentially methylated imprint control regions (ICRs) regulate the monoallelic expression of imprinted genes. Their epigenetic dysregulation by environmental exposures throughout life results in the formation of common chronic diseases. Unfortunately, existing Infinium methylation arrays lack the ability to profile these regions adequately. Whole genome bisulfite sequencing (WGBS) is the unique method able to profile the ICRs. However, it is very expensive and it requires not only a high coverage, but it is also computationally intensive to assess these regions. Findings To address this deficiency, we developed a custom methylation array containing 22,819 probes. Among them, 10,438 are CG probes targeting unique CpG sites, with 9,757 probes successfully mapping to 1,088 out of the 1,488 candidate ICRs recently described. To assess the performance of the array, we created matched samples processed with the Human Imprintome array and WGBS, which is the current standard method for assessing the methylation of the Human Imprintome. We compared the methylation levels from the shared CpG sites, and obtained a mean R2 = 0.569. We also created matched samples processed with the Human Imprintome array and the Infinium Methylation EPIC v2 array, and obtained a mean R2 = 0.796. Furthermore, replication experiments demonstrated high reliability (ICC: 0.799–0.945). Conclusions Our custom array will be useful for replicable and accurate assessment, mechanistic insight, and targeted investigation of ICRs. This tool should accelerate the discovery of ICRs associated with a wide range of diseases and exposures, and advance our understanding of genomic imprinting and its relevance in development and disease formation throughout the life course.

Abstract Background Paternal allele-specific DNA methylation of the imprinting control region (H19 ICR) controls genomic imprinting at the Igf2/H19 locus. We previously demonstrated that the mouse H19 ICR transgene acquires imprinted DNA methylation in preimplantation mouse embryos. This activity is also present in the endogenous H19 ICR and protects it from genome-wide reprogramming after fertilization. We also identified a 118-bp sequence within the H19 ICR that is responsible for post-fertilization imprinted methylation. Two mutations, one in the five RCTG motifs and the other a 36-bp deletion both in the 118-bp segment, caused complete and partial loss, respectively, of methylation following paternal transmission in each transgenic mouse. Interestingly, these mutations overlap with the binding site for the transcription factor Kaiso, which is reportedly involved in maintaining paternal methylation at the human H19 ICR (IC1) in cultured cells. In this study, we investigated if Kaiso regulates imprinted DNA methylation of the H19 ICR in vivo. Results Neither Kaiso deletion nor mutation of Kaiso binding sites in the 118-bp region affected DNA methylation of the mouse H19 ICR transgene. The endogenous mouse H19 ICR was methylated in a wild-type manner in Kaiso-null mutant mice. Additionally, the human IC1 transgene acquired imprinted DNA methylation after fertilization in the absence of Kaiso. Conclusions Our results indicate that Kaiso is not essential for either post-fertilization imprinted DNA methylation of the transgenic H19 ICR in mouse or for methylation imprinting of the endogenous mouse H19 ICR.

Abstract Background Optimal size at birth dictates perinatal survival and long-term risk of developing common disorders such as obesity, type 2 diabetes and cardiovascular disease. The imprinted Grb10 gene encodes a signalling adaptor protein capable of inhibiting receptor tyrosine kinases, including the insulin receptor (Insr) and insulin-like growth factor type 1 receptor (Igf1r). Grb10 restricts fetal growth such that Grb10 knockout (KO) mice are at birth some 25-35% larger than wild type. Using a mouse genetic approach, we test the widely held assumption that Grb10 influences growth through interaction with Igf1r, which has a highly conserved growth promoting role. Results Should Grb10 interact with Igf1r to regulate growth Grb10:Igf1r double mutant mice should be indistinguishable from Igf1r KO single mutants, which are around half normal size at birth. Instead, Grb10:Igf1r double mutants were intermediate in size between Grb10 KO and Igf1r KO single mutants, indicating additive effects of the two signalling proteins having opposite actions in separate pathways. Some organs examined followed a similar pattern, though Grb10 KO neonates exhibited sparing of the brain and kidneys, whereas the influence of Igf1r extended to all organs. An interaction between Grb10 and Insr was similarly investigated. While there was no general evidence for a major interaction for fetal growth regulation, the liver was an exception. The liver in Grb10 KO mutants was disproportionately overgrown with evidence of excess lipid storage in hepatocytes, whereas Grb10:Insr double mutants were indistinguishable from Insr single mutants or wild types. Conclusions Grb10 acts largely independently of Igf1r or Insr to control fetal growth and has a more variable influence on individual organs. Only the disproportionate overgrowth and excess lipid storage seen in the Grb10 KO neonatal liver can be explained through an interaction between Grb10 and the Insr. Our findings are important for understanding how positive and negative influences on fetal growth dictate size and tissue proportions at birth.

Haplotype‐resolved 3D chromatin architecture related to allelic differences in avian skeletal muscle development has not been addressed so far, although chicken husbandry for meat consumption has been prevalent feature of cultures on every continent for more than thousands of years. Here, high‐resolution Hi‐C diploid maps (1.2‐kb maximum resolution) are generated for skeletal muscle tissues in chicken across three developmental stages (embryonic day 15 to day 30 post‐hatching). The sequence features governing spatial arrangement of chromosomes and characterize homolog pairing in the nucleus, are identified. Multi‐scale characterization of chromatin reorganization between stages from myogenesis in the fetus to myofiber hypertrophy after hatching show concordant changes in transcriptional regulation by relevant signaling pathways. Further interrogation of parent‐of‐origin‐specific chromatin conformation supported that genomic imprinting is absent in birds. This study also reveals promoter‐enhancer interaction (PEI) differences between broiler and layer haplotypes in skeletal muscle development‐related genes are related to genetic variation between breeds, however, only a minority of breed‐specific variations likely contribute to phenotypic divergence in skeletal muscle potentially via allelic PEI rewiring. Beyond defining the haplotype‐specific 3D chromatin architecture in chicken, this study provides a rich resource for investigating allelic regulatory divergence among chicken breeds. [ABSTRACT FROM AUTHOR]

DNA methylation, an epigenetic mechanism that alters gene expression without changing DNA sequence, is essential for organism development and key biological processes like genomic imprinting and X‐chromosome inactivation. Despite tremendous efforts in DNA methylation research, accurate quantification of cytosine methylation remains a challenge. Here, a single‐base methylation quantification approach is introduced by weighting methylation of consecutive CpG sites (Wemics) in genomic regions. Wemics quantification of DNA methylation better predicts its regulatory impact on gene transcription and identifies differentially methylated regions (DMRs) with more biological relevance. Most Wemics‐quantified DMRs in lung cancer are epigenetically conserved and recurrently occurred in other primary cancers from The Cancer Genome Atlas (TCGA), and their aberrant alterations can serve as promising pan‐cancer diagnostic markers. It is further revealed that these detected DMRs are enriched in transcription factor (TF) binding motifs, and methylation of these TF binding motifs and TF expression synergistically regulate target gene expression. Using Wemics on epigenomic‐transcriptomic data from the large lung cancer cohort, a dozen novel genes with oncogenic potential are discovered that are upregulated by hypomethylation but overlooked by other quantification methods. These findings increase the understanding of the epigenetic mechanism by which DNA methylation regulates gene expression. [ABSTRACT FROM AUTHOR]

Background: Paternal allele-specific DNA methylation of the imprinting control region (H19 ICR) controls genomic imprinting at the Igf2/H19 locus. We previously demonstrated that the mouse H19 ICR transgene acquires imprinted DNA methylation in preimplantation mouse embryos. This activity is also present in the endogenous H19 ICR and protects it from genome-wide reprogramming after fertilization. We also identified a 118-bp sequence within the H19 ICR that is responsible for post-fertilization imprinted methylation. Two mutations, one in the five RCTG motifs and the other a 36-bp deletion both in the 118-bp segment, caused complete and partial loss, respectively, of methylation following paternal transmission in each transgenic mouse. Interestingly, these mutations overlap with the binding site for the transcription factor Kaiso, which is reportedly involved in maintaining paternal methylation at the human H19 ICR (IC1) in cultured cells. In this study, we investigated if Kaiso regulates imprinted DNA methylation of the H19 ICR in vivo. Results: Neither Kaiso deletion nor mutation of Kaiso binding sites in the 118-bp region affected DNA methylation of the mouse H19 ICR transgene. The endogenous mouse H19 ICR was methylated in a wild-type manner in Kaiso-null mutant mice. Additionally, the human IC1 transgene acquired imprinted DNA methylation after fertilization in the absence of Kaiso. Conclusions: Our results indicate that Kaiso is not essential for either post-fertilization imprinted DNA methylation of the transgenic H19 ICR in mouse or for methylation imprinting of the endogenous mouse H19 ICR. [ABSTRACT FROM AUTHOR]

Epigenetic control systems are based on chromatin modifications (DNA methylation, histone modifications and nucleosome positioning), which affect the local kinetics of gene expression. They play an important role in maintaining cell fate decisions, X inactivation and genomic imprinting. Aberrant chromatin states that are associated with a deleterious change in gene expression are called epimutations. An epimutation can be a primary epimutation that has occurred in the absence of any genetic change or a secondary epimutation that results from a mutation of a cis-acting regulatory element or trans-acting factor. Epimutations may play a causative role in disease, for example in imprinting disorders, or may be part of the pathogenetic mechanism as in the fragile X syndrome and in syndromes caused by a mutation affecting a chromatin modifier. For several diseases, DNA methylation testing is an important tool in the diagnostic work-up of patients. [ABSTRACT FROM AUTHOR]

Background: In Egypt, where research into the underlying cytogenetic and molecular causes of infertility is scarce, unexplained infertility presents a substantial clinical and emotional difficulty for many couples. This study attempts to fill a gap in knowledge on the chromosomal disorders that cause infertility in Egyptian couples. Methods: In order to compile research on cytogenetic and molecular anomalies in Egyptian couples with unexplained infertility, an extensive database search was performed. Translocations, inversions, and aneuploidies were the primary focus of this study. Studies discussing the diagnostic utility of chromosomal analysis and molecular markers were considered and critically appraised up to April 2023 for this review. Results: The results suggest that cytogenetic and molecular abnormalities are responsible for a significant proportion of unexplained infertility in Egypt. Disruption of gametogenesis, abnormal embryonic development, and problems with genomic imprinting have all been linked to chromosomal abnormalities, which are typically missed in routine infertility examinations. Improved understanding of the causes of infertility and the potential for individualized therapies has resulted from the development of genetic testing. Conclusions: There is a strong correlation between cytogenetic and molecular abnormalities and unexplained infertility in Egypt. It becomes clear that karyotypic and molecular chromosomal examination are essential parts of the diagnostic process for afflicted couples. This analysis highlights the need for improved diagnosis techniques and the creation of individualized treatments. The ethical implications of genetic testing and Assisted reproductive technology are substantial, calling for a careful weighing of technology advantages and moral issues. New genetic and chromosomal therapies show promise in reducing infertility problems, and they fit in with current trends in ethics, medicine, and scientific inquiry. Future Directions: Future research in reproductive genetics should aim to improve diagnosis accuracy and provide therapies that are targeted to individual genetic profiles. There is a need for both ethical norms and instructional initiatives to help couples make informed choices about genetic testing and reproductive treatments. [ABSTRACT FROM AUTHOR]

Paternal genome elimination (PGE) is a non-Mendelian inheritance system, described in numerous arthropod species, in which males develop from fertilized eggs, but their paternally inherited chromosomes are eliminated before or during spermatogenesis. Therefore, PGE males only transmit their maternally inherited set of chromosomes to their offspring. In addition to the elimination of paternal chromosomes, diverse PGE species have also repeatedly evolved the transcriptional silencing of the paternal genome, making males effectively haploid. However, it is unclear if this paternal chromosome silencing is mechanistically linked to the chromosome elimination or has evolved at a later stage, and if so, what drives the haploidization of males under PGE. In order to understand these questions, here we study the human louse, Pediculus humanus , which represents an ideal model system, as it appears to be the only instance of PGE where males eliminate, but not silence their paternal chromosomes, although the latter remains to be shown conclusively. In this study, we analyzed parent-of-origin allele-specific expression patterns in male offspring of crosses between head and body lice ecotypes. We show that hybrid adult males of P. humanus display biparental gene expression, which constitutes the first case of a species with PGE in which genetic activity of paternal chromosomes in the soma is not affected by embryonic silencing or (partial or complete) elimination. We did however also identify a small number of maternally biased genes (potentially imprinted genes), which may be involved in the elimination of paternal chromosomes during spermatogenesis. Finally, we have identified genes that show ecotype-specific expression bias. Given the low genetic diversity between ecotypes, this is suggestive for a role of epigenetic processes in ecotype differences. [ABSTRACT FROM AUTHOR]

Genomic imprinting is an epigenetic regulation in mammals in which a small subset of genes is monoallelically expressed dependent on their parental origin. A large imprinted domain, SGCE/PEG10 locus, is located on human chromosome 7q21s and mouse proximal chromosome 6. However, genomic imprinting of bovine SGCE/PEG10 cluster has not been systematically studied. In this study, we investigated allele expression of 14 genes of the SGCE/PEG10 locus in bovine somatic tissues and term placenta using a single nucleotide polymorphism (SNP)‐based sequencing method. In addition to SGCE and PEG10, two conserved paternally expressed genes in human and mice, five other genes (TFPI2, GNG11, ASB4, PON1, and PON3) were paternally expressed. Three genes, BET1, COL1A2, and CASD1, exhibited tissue‐specific monoallelic expression. CALCR showed monoallelic expression in tissues but biallelic expression in the placenta. Three genes, GNGT1, PPP1R9A, and PON2, showed biallelic expression in cattle. Five differentially methylated regions (DMRs) were found to be associated with the allelic expression of TFPI2, COL1A2, SGCE/PEG10, PON3, and ASB4 genes, respectively. The SGCE/PEG10 DMR is a maternally hypermethylated germline DMR, but TFPI2, COL1A2, PON3, and ASB4 DMRs are secondary DMRs. In summary, we identified five novel bovine imprinted genes (GNG11, BET1, COL1A2, CASD1, and PON1) and four secondary DMRs at the SGCE/PEG10 locus. [ABSTRACT FROM AUTHOR]

Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important role in Histone 3 Lysine 27 trimethylation (H3K27me3)-dependent imprinting, loss of which leads to growth and developmental changes in mouse offspring. In this study, we show that offspring from mouse oocytes lacking the PRC2 protein Embryonic Ectoderm Development (EED) were initially developmentally delayed, characterised by low blastocyst cell counts and substantial growth delay in mid-gestation embryos. This initial developmental delay was resolved as offspring underwent accelerated fetal development and growth in late gestation resulting in offspring that were similar stage and weight to controls at birth. The accelerated development and growth in offspring from Eed-null oocytes was associated with remodelling of the placenta, which involved an increase in fetal and maternal tissue size, conspicuous expansion of the glycogen-enriched cell population, and delayed parturition. Despite placental remodelling and accelerated offspring fetal growth and development, placental efficiency, and fetal blood glucose levels were low, and the fetal blood metabolome was unchanged. Moreover, while expression of the H3K27me3-imprinted gene and amino acid transporter Slc38a4 was increased, fetal blood levels of individual amino acids were similar to controls, indicating that placental amino acid transport was not enhanced. Genome-wide analyses identified extensive transcriptional dysregulation and DNA methylation changes in affected placentas, including a range of imprinted and non-imprinted genes. Together, while deletion of Eed in growing oocytes resulted in fetal growth and developmental delay and placental hyperplasia, our data indicate a remarkable capacity for offspring fetal growth to be normalised despite inefficient placental function and the loss of H3K27me3-dependent genomic imprinting. [ABSTRACT FROM AUTHOR]

Genomic imprinting plays an important role in the growth and development of mammals. When the original imprint status of these genes is lost, known as loss of imprinting (LOI), it may affect growth, neurocognitive development, metabolism, and even tumor susceptibility. The LOI of imprint genes has gradually been found not only as an early event in tumorigenesis, but also to be involved in progression. More than 120 imprinted genes had been identified in humans. In this review, we summarized the most studied LOI of two gene clusters and 13 single genes in cancers. We focused on the roles they played, that is, as growth suppressors and anti-apoptosis agents, sustaining proliferative signaling or inducing angiogenesis; the molecular pathways they regulated; and especially their clinical significance. It is notable that 12 combined forms of multi-genes' LOI, 3 of which have already been used as diagnostic models, achieved good sensitivity, specificity, and accuracy. In addition, the methods used for LOI detection in existing research are classified into detection of biallelic expression (BAE), differentially methylated regions (DMRs), methylation, and single-nucleotide polymorphisms (SNPs). These all indicated that the detection of imprinting genes' LOI has potential clinical significance in cancer diagnosis, treatment, and prognosis. [ABSTRACT FROM AUTHOR]

Introduction: Myotonic dystrophy type 1 (DM1) is a hereditary neuromuscular disorder affecting the central nervous system (CNS). Although sex differences have been explored in other neuromuscular disorders, research on this topic in DM1 remains limited. The present study aims to analyze sex differences (both the patient's and disease-transmitting parent's sex) with a focus on CNS outcomes. Methods: Retrospective data from 146 non-congenital DM1 patients were analyzed, including clinical, molecular, neuropsychological, and neuroradiological data. Sex and inheritance pattern differences were analyzed using t-tests, and ANOVA analyses were conducted to address the interactions. Results: Overall, no significant sex differences were observed except in certain cognitive domains. However, individuals with maternal inheritance showed larger CTG expansion size, lower estimated IQs, and poorer performance on visual memory, executive functions, and language domains than those with paternal inheritance. Notably, IQ performance was independently influenced by inheritance pattern and CTG expansion. Discussion: This study is the first to delve into sex differences in DM1 with a focus on CNS outcomes. While the results revealed the absence of a sex-specific clinicmolecular profile, more substantial CNS differences were observed between patients with maternal and paternal inheritance patterns. The hypothetical existence of genomic imprinting and its potential mechanism are discussed. These findings hold potential implications for aiding clinical management by improving genetic counseling and predicting disease severity and prognosis. [ABSTRACT FROM AUTHOR]

Background: Temple syndrome (TS14) is a rare imprinting disorder caused by maternal UPD14, imprinting defects or paternal microdeletions which lead to an increase in the maternal expressed genes and a silencing the paternally expressed genes in the 14q32 imprinted domain. Classical TS14 phenotypic features include pre- and postnatal short stature, small hands and feet, muscular hypotonia, motor delay, feeding difficulties, weight gain, premature puberty along and precocious puberty. Methods: An exon array comparative genomic hybridization was performed on a patient affected by psychomotor and language delay, muscular hypotonia, relative macrocephaly, and small hand and feet at two years old. At 6 years of age, the proband presented with precocious thelarche. Genes dosage and methylation within the 14q32 region were analyzed by MS-MLPA. Bisulfite PCR and pyrosequencing were employed to quantification methylation at the four known imprinted differentially methylated regions (DMR) within the 14q32 domain: DLK1 DMR, IG-DMR, MEG3 DMR and MEG8 DMR. Results: The patient had inherited a 69 Kb deletion, encompassing the entire DLK1 gene, on the paternal allele. Relative hypermethylation of the two maternally methylated intervals, DLK1 and MEG8 DMRs, was observed along with normal methylation level at IG-DMR and MEG3 DMR, resulting in a phenotype consistent with TS14. Additional family members with the deletion showed modest methylation changes at both the DLK1 and MEG8 DMRs consistent with parental transmission. Conclusion: We describe a girl with clinical presentation suggestive of Temple syndrome resulting from a small paternal 14q32 deletion that led to DLK1 whole-gene deletion, as well as hypermethylation of the maternally methylated DLK1-DMR. [ABSTRACT FROM AUTHOR]

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder that exhibits etiologic genomic imprinting characterized by molecular heterogeneity and phenotypic variability. Associations with localized developmental dysplastic chondromatous lesions and cortical neuronal heterotopias have not previously been described. A 33-week gestational age female had an omphalocele and intractable hypoglycemia at birth. The placenta demonstrated placental mesenchymal dysplasia. Detection of hypermethylation of IC1 and hypomethylation of IC2 confirmed Beckwith-Wiedemann syndrome, most likely due to uniparental disomy. Additional findings included right mid-tibial and right 5–8th developmental dysplastic chondromatous lesions, absent corpus callosum and numerous right-sided cortical neuronal heterotopias, right hemihypertrophy, multiple cystic hepatic mesenchymal hamartomas and hepatic infantile hemangiomas, nisidioblastosis and cystic pancreatic lesions. The infant died with multi-organ failure and anasarca at 7 weeks of life. Beckwith-Wiedemann syndrome anomalies may include multifocal developmental dysplastic chondromatous lesions and cerebral neuronal heterotopias, lateralized, and corpus callosum aplasia. [ABSTRACT FROM AUTHOR]

Goats have achieved global prominence as essential livestock since their initial domestication, primarily owing to their remarkable adaptability to diverse environmental and production systems. Differential selection pressures influenced by climate have led to variations in their physical attributes, leaving genetic imprints within the genomes of goat breeds raised in diverse agroecological settings. In light of this, our study pursued a comprehensive analysis, merging environmental data with single nucleotide polymorphism (SNP) variations, to unearth indications of selection shaped by climate-mediated forces in goats. Through the examination of 43,300 SNPs from 51 indigenous goat breeds adapting to different climatic conditions using four analytical methods: latent factor mixed models (LFMM), F-statistics (Fst), Extended haplotype homozygosity across populations (XPEHH), and spatial analysis method (SAM), A total of 74 genes were revealed to display clear signs of selection, which are believed to be influenced by climatic conditions. Among these genes, 32 were consistently identified by at least two of the applied methods, and three genes (DENND1A, PLCB1, and ITPR2) were confirmed by all four approaches. Moreover, our investigation yielded 148 Gene Ontology (GO) terms based on these 74 genes, underlining pivotal biological pathways crucial for environmental adaptation. These pathways encompass functions like vascular smooth muscle contraction, cellular response to heat, GTPase regulator activity, rhythmic processes, and responses to temperature stimuli. Of significance, GO terms about endocrine regulation and energy metabolic responses, key for local adaptation were also uncovered, including biological processes, such as cell differentiation, regulation of peptide hormone secretion, and lipid metabolism. These findings contribute to our knowledge of the genetic structure of climate-triggered adaptation across the goat genome and have practical implications for marker-assisted breeding in goats. [ABSTRACT FROM AUTHOR]

Allele-specific methylation (ASM) is an epigenetic modification whereby one parental allele becomes methylated and the other unmethylated at a specific locus. ASM is most often driven by the presence of nearby heterozygous variants that influence methylation, but also occurs somatically in the context of genomic imprinting. In this study, we investigate ASM using publicly available single-cell reduced representation bisulfite sequencing (scRRBS) data on 608 B cells sampled from six healthy B cell samples and 1,230 cells from 11 chronic lymphocytic leukemia (CLL) samples. We developed a likelihood-based criterion to test whether a CpG exhibited ASM, based on the distributions of methylated and unmethylated reads both within and across cells. Applying our likelihood ratio test, 65,998 CpG sites exhibited ASM in healthy B cell samples according to a Bonferroni criterion (p < 8.4 × 10−9), and 32,862 CpG sites exhibited ASM in CLL samples (p < 8.5 × 10−9). We also called ASM at the sample level. To evaluate the accuracy of our method, we called heterozygous variants from the scRRBS data, which enabled variant-based calls of ASM within each cell. Comparing sample-level ASM calls to the variant-based measures of ASM, we observed a positive predictive value of 76%–100% across samples. We observed high concordance of ASM across samples and an overrepresentation of ASM in previously reported imprinted genes and genes with imprinting binding motifs. Our study demonstrates that single-cell bisulfite sequencing is a potentially powerful tool to investigate ASM, especially as studies expand to increase the number of samples and cells sequenced. We developed a method to infer allele-specific methylation from single-cell bisulfite sequencing data and applied this approach to data derived from healthy B cell and chronic lymphocytic leukemia samples. Our method performed well compared to an approach dependent on nearby genetic variants and identified sites that preferentially overlapped imprinted genes. [ABSTRACT FROM AUTHOR]

22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA microsatellite markers and single-nucleotide polymorphisms (SNPs). Among the 61 individuals, 29 (47.5%) had a maternal origin of the deletion, and 32 (52.5%) a paternal origin. Comparison of the frequency of the main clinical features between individuals with deletions of maternal or paternal origin showed no statistically significant difference. However, Truncus arteriosus, pulmonary atresia, seizures, and scoliosis were only found in patients with deletions of maternal origin. Also, a slight difference in the frequency of other clinical features between groups of maternal or paternal origin was noted, including congenital heart disease, endocrinological alterations, and genitourinary abnormalities, all of them more common in patients with deletions of maternal origin. Although parental origin of the deletion does not seem to contribute to the phenotypic variability of most clinical signs observed in 22q11.2DS, these findings suggest that patients with deletions of maternal origin could have a more severe phenotype. Further studies with larger samples focusing on these specific features could corroborate these findings. [ABSTRACT FROM AUTHOR]

This article is an interview with Dr. Stefan Stricker, a prominent researcher in cellular reprogramming. Dr. Stricker discusses his research on cell identity conversion and its applications in regenerative medicine. He explains his laboratory's innovative approaches, such as using CRISPR and single-cell sequencing, to study epigenetic barriers and gene expression. Dr. Stricker's work has implications for understanding cancer development, rejuvenating aged stem cells, and improving cell reprogramming techniques. The article also discusses experiments conducted by the authors using a method called Collide-Seq, which revealed insights into the regulation of fibroblast genes and the resolution of cell identity conflicts. The authors highlight the concept of dominance in cell fusion experiments and the potential for future research in cellular reprogramming. [Extracted from the article]

Background: The 15q11–q13 region is a genetic locus with genes subject to genomic imprinting, significantly influencing neurodevelopment. Genomic imprinting is an epigenetic phenomenon that causes differential gene expression based on the parent of origin. In most diploid organisms, gene expression typically involves an equal contribution from both maternal and paternal alleles, shaping the phenotype. Nevertheless, in mammals, including humans, mice, and marsupials, the functional equivalence of parental alleles is not universally maintained. Notably, during male and female gametogenesis, parental alleles may undergo differential marking or imprinting, thereby modifying gene expression without altering the underlying DNA sequence. Neurodevelopmental disorders, such as Prader–Willi syndrome (PWS) (resulting from the absence of paternally expressed genes in this region), Angelman syndrome (AS) (associated with the absence of the maternally expressed UBE3A gene), and 15q11–q13 duplication syndrome (resulting from the two common forms of duplications—either an extra isodicentric 15 chromosome or an interstitial 15 duplication), are the outcomes of genetic variations in this imprinting region. Methods: Conducted a genomic study to identify the frequency of pathogenic variants impacting the 15q11–q13 region in an ethnically homogenous population from Bangladesh. Screened all known disorders from the DECIPHER database and identified variant enrichment within this cohort. Using the Horizon analysis platform, performed enrichment analysis, requiring at least >60% overlap between a copy number variation and a disorder breakpoint. Deep clinical phenotyping was carried out through multiple examination sessions to evaluate a range of clinical symptoms. Results: This study included eight individuals with clinically suspected PWS/AS, all previously confirmed through chromosomal microarray analysis, which revealed chromosomal breakpoints within the 15q11–q13 region. Among this cohort, six cases (75%) exhibited variable lengths of deletions, whereas two cases (25%) showed duplications. These included one type 2 duplication, one larger atypical duplication, one shorter type 2 deletion, one larger type 1 deletion, and four cases with atypical deletions. Furthermore, thorough clinical assessments led to the diagnosis of four PWS patients, two AS patients, and two individuals with 15q11–q13 duplication syndrome. Conclusion: Our deep phenotypic observations identified a spectrum of clinical features that overlap and are unique to PWS, AS, and Dup15q syndromes. Our findings establish genotype–phenotype correlation for patients impacted by variable structural variations within the 15q11–q13 region. [ABSTRACT FROM AUTHOR]

Danger requires a strong rapid response. Speedy triggers are prone to false signals. False alarms can be costly, requiring strong negative regulators to oppose the initial triggers. Strongly opposed forces can easily be perturbed, leading to imbalance and disease. For example, immunity and fear response balance strong rapid triggers against widespread slow negative regulators. Diseases of immunity and behavior arise from imbalance. A different opposition of forces occurs in mammalian growth, which balances strong paternally expressed accelerators against maternally expressed suppressors. Diseases of overgrowth or undergrowth arise from imbalance. Other examples of opposing forces and disease include control of dopamine expression and male versus female favored traits.

We report a 4-year-old girl with neurodevelopmental abnormalities who has maternal uniparental isodisomy of chromosome 2 leading to homozygosity for a likely pathogenic variant in SPR, and a variant of uncertain significance in ZNF142. Biallelic pathogenic variants in SPR lead to sepiapterin reductase deficiency (SRD), a dopa-responsive dystonia. Pathogenic variants in ZNF142 are associated with an autosomal recessive neurodevelopmental disorder characterized by impaired speech and hyperkinetic movements, which has significant clinical overlap with SRD. Our patient showed dramatic improvement in motor skills after treatment with levodopa. We also reviewed 67 published reports of uniparental disomy of chromosome 2 (UPD2) associated with various clinical outcomes. These include autosomal recessive disorders associated with loci on chromosome 2, infants with UPD2 whose gestations were associated with confined placental mosaicism for trisomy 2 leading to intrauterine growth restriction with good postnatal catchup growth, and normal phenotypes in children and adults with an incidental finding of either maternal or paternal UPD2. These latter reports provide support for the conclusion that genes located on chromosome 2 are not subject to imprinting. We also explore the mechanisms giving rise to UPD2.

According to sociologist, Sylvia patriarchy is “a system of social structures and practices in which men dominate, oppress, and exploit women.” Derived from the Greek word patriarkhēs, patriarchy means “the rule of the father.” American sociologist Allan Johnson further mentions that patriarchy is a kind of society in which even though men and women participate, but is male-privileged, maledominated, male-identified, and male-centered. Apart from the sociologist’s point of view of society, it seems that developmental programs in biology also have a patriarchal trend. At least, that’s what is reported from several studies recently. Lopez-Tello et al., reported a paternal insulinlike growth factor 2 (Igf2)-related selective trafficking of maternal resources toward the fetus for its development. Metabolic demands for the fetus are enhanced during pregnancy. It is, therefore, observed that there is a relatively greater shunting of metabolic fuels toward the fetus to increase nutrient availability, more than it is perhaps allowed by the maternal system. The placenta assists in this shuttle by promoting insulin resistance, which leads to glucose intolerance in the mother. This glucose is now made available to the fetal compartments. The paternal Igf2 gene undergoes genomic imprinting, and only the copy inherited from the father is active. Paternally active Igf2 expressed in placental endocrine cells directs the maternal lipids and carbohydrates toward the fetus, an excellent example of paternal manipulation of maternal physiology and metabolic patriarchy. Further, studies have shown that fathers fed with a high-fat diet reduce the pregnancy success rate because of the reduction of their sperm motility. Excess intake of processed food, highsugar diets, or fructose has consequences on offspring’s cardiovascular and metabolic diseases. Males fed a low protein diet in mice results in glucose intolerance, metabolic and cardiovascular dysfunctions, and altered patterns of bone mineralization in pups. We, therefore, can conclude a robust paternal influence on pregnancy and fetal outcome. Pregnancy was once thought of as an exclusively maternal affair. Increasing research in this arena seems to have smashed that stereotype with paternal influence seems to play a significant role in shaping the birth process. It is high time that Sylvia patriarchal understanding is redefined with the paternal share of responsibility beyond just dominance and an authoritarian role.

ABSTRACTPenile squamous cell carcinoma (SCC) is a rare and aggressive tumour mainly related to lifestyle behaviour and human papillomavirus (HPV) infection. Environmentally induced loss of imprinting (LOI) at the H19 differentially methylated region (H19DMR) is associated with many cancers in the early events of tumorigenesis and may be involved in the pathogenesis of penile SCC. We sought to evaluate the DNA methylation pattern at H19DMR and its association with HPV infection in men with penile SCC by bisulfite sequencing (bis-seq). We observed an average methylation of 32.2% ± 11.6% at the H19DMR of penile SCC and did not observe an association between the p16INK4a+ (p = 0.59) and high-risk HPV+ (p = 0.338) markers with methylation level. The average methylation did not change according to HPV positive for p16INK4a+ or hrHPV+ (35.4% ± 10%) and negative for both markers (32.4% ± 10.1%) groups. As the region analysed has a binding site for the CTCF protein, the hypomethylation at the surrounding CpG sites might alter its insulator function. In addition, there was a positive correlation between intense polymorphonuclear cell infiltration and hypomethylation at H19DMR (p = 0.035). Here, we report that hypomethylation at H19DMR in penile SCC might contribute to tumour progression and aggressiveness regardless of HPV infection.

Background: Beckwith–Wiedemann syndrome (BWS) is a genomic imprinting disorder caused by diverse genetic and/or epigenetic disorders of chromosome 11p15.5. BWS presents with a variety of clinical features, including overgrowth and an increased risk of embryonal tumors. Notably however, reports of patients with BWS and breast tumors are rare, and the association between these conditions is still unclear. Insulin-like growth factor-2 (IGF2) expression is known to be associated with the development of various cancers, including breast cancer, and patients with BWS with specific subtypes of molecular defects are known to show characteristic clinical features and IGF2 overexpression. Case presentation: A 17-year-old girl who had been diagnosed with BWS based on an umbilical hernia, hyperinsulinemia, and left hemihypertrophy at birth, visited our department with a gradually swelling left breast. Her left breast was markedly larger than her right breast on visual examination. Imaging examinations showed two tumors measuring about 10 cm each in the left breast, and she was diagnosed with juvenile fibroadenoma following core needle biopsy. The two breast tumors were removed surgically and the patient remained alive with no recurrence. The final diagnosis was juvenile fibroadenoma without malignant findings. Immunohistochemical staining using IGF2 antibody revealed overexpression of IGF2 in the cytoplasm of ductal epithelial cells. Because of her clinical features and IGF2 overexpression, molecular defects of 11p15.5 including a possible genetic background of paternal uniparental disomy of chromosome 11 or hypermethylation of imprinting center 1 was suspected. Conclusions: In this case, overexpression of IGF2 suggested a possible relationship between BWS and breast tumors. Moreover, the characteristic clinical features and IGF2 staining predicted the subtype of 11p15.5 molecular defects in this patient. [ABSTRACT FROM AUTHOR]

DNA methylation (DNAme) has long been recognized as a host defense mechanism, both in the restriction modification systems of prokaryotes as well as in the transcriptional silencing of repetitive elements in mammals. When DNAme was shown to be implicated as a key epigenetic mechanism in the regulation of imprinted genes in mammals, a parallel with host defense mechanisms was drawn, suggesting perhaps a common evolutionary origin. Here we review recent work related to this hypothesis on two different aspects of the developmental imprinting cycle in mammals that has revealed unexpected roles for long terminal repeat (LTR) retroelements in imprinting, both canonical and noncanonical. These two different forms of genomic imprinting depend on different epigenetic marks inherited from the mature gametes, DNAme and histone H3 lysine 27 trimethylation (H3K27me3), respectively. DNAme establishment in the maternal germline is guided by transcription during oocyte growth. Specific families of LTRs, evading silencing mechanisms, have been implicated in this process for specific imprinted genes. In noncanonical imprinting, maternally inherited histone marks play transient roles in transcriptional silencing during preimplantation development. These marks are ultimately translated into DNAme, notably over LTR elements, for the maintenance of silencing of the maternal alleles in the extraembryonic trophoblast lineage. Therefore, LTR retroelements play important roles in both establishment and maintenance of different epigenetic pathways leading to imprinted expression during development. Because such elements are mobile and highly polymorphic among different species, they can be coopted for the evolution of new species-specific imprinted genes. [ABSTRACT FROM AUTHOR]

Polycomb group (PcG) proteins are a subset of epigenetic factors that are highly conserved throughout evolution. In mammals, PcG proteins can be classified into two muti-proteins complexes: Polycomb repressive complex 1 (PRC1) and PRC2. Increasing evidence has demonstrated that PcG complexes play critical roles in the regulation of gene expression, genomic imprinting, chromosome X-inactivation, and chromatin structure. Accordingly, the dysfunction of PcG proteins is tightly orchestrated with abnormal developmental processes. Here, we summarized and discussed the current knowledge of the biochemical and molecular functions of PcG complexes, especially the PRC1 and PRC2 in mammalian development including embryonic development and tissue development, which will shed further light on the deep understanding of the basic knowledge of PcGs and their functions for reproductive health and developmental disorders. [ABSTRACT FROM AUTHOR]

Genomic imprinting is an epigenetically-regulated process of central importance in mammalian development and evolution. It involves multiple levels of regulation, with spatio-temporal heterogeneity, leading to the contextdependent and parent-of-origin specific expression of a small fraction of the genome. Genomic imprinting studies have therefore been essential to increase basic knowledge in functional genomics, evolution biology and developmental biology, as well as with regard to potential clinical and agrigenomic perspectives. Here we offer an overview on the contribution of livestock research, which features attractive resources in several respects, for better understanding genomic imprinting and its functional impacts. Given the related broad implications and complexity, we promote the use of such resources for studying genomic imprinting in a holistic and integrative view. We hope this mini-review will draw attention to the relevance of livestock genomic imprinting studies and stimulate research in this area. [ABSTRACT FROM AUTHOR]

Crossbreeding plays a pivotal role within pig breeding programmes, aiming to maximize heterosis and improve reproductive traits in crossbred maternal lines. Nevertheless, there is evidence indicating that the performance of reciprocal crosses between two genetic lines might exhibit variability. These variations in performance can be attributed to differences in the correlations between gametic effects, acting as either sire or dam, within purebred and crossbred populations. To address this issue, we propose a multivariate gametic model that incorporates up to four correlated gametic effects for each parental population. The model is employed on a data set comprising litter size data (total number of piglets born—TNB‐ and number of piglets born alive—NBA‐) derived from a reciprocal cross involving two Iberian pig populations: Entrepelado and Retinto. The data set comprises 6933 records from 1564 purebred Entrepelado (EE) sows, 4995 records from 1015 Entrepelado × Retinto (ER) crosses, 2977 records from 756 Retinto × Entrepelado (RE) crosses and 7497 records from 1577 purebred Retinto (RR) sows. The data set is further supplemented by a pedigree encompassing 6007 individual‐sire‐dam entries. The statistical model also included the order of parity (with six levels), the breed of the service sire (five levels) and the herd‐year‐season effects (141 levels). Additionally, the model integrates random dominant and permanent environmental sow effects. The analysis employed a Bayesian approach, and the results revealed all the posterior estimates of the gametic correlations to be positive. The range of the posterior mean estimates of the correlations varied across different gametic effects and traits, with a range between 0.04 (gametic correlation between the paternal effects for purebred and the maternal for crossbred in Retinto) and 0.53 (gametic correlation between the paternal effects for purebred and the paternal for crossbred in Entrepelado). Furthermore, the posterior mean variance estimates of the maternal gametic effects were consistently surpassed those for paternal effects within all four populations. The results suggest the possible influence of imprinting effects on the genetic control of litter size, and underscore the importance of incorporating crossbred data into the breeding value predictions for purebred individuals. [ABSTRACT FROM AUTHOR]

Genomic imprinting refers to allele-specific expression of genes depending on parental origin, and it is regulated by epigenetic modifications. Intraspecific allelic variation for imprinting has been detected; however, the intraspecific genome-wide allelic epigenetic variation in maize and its correlation with imprinting variants remain unclear. Here, three reciprocal hybrids were generated by crossing Zea mays inbred lines CAU5, B73, and Mo17 in order to examine the intraspecific conservation of the imprinted genes in the kernel. The majority of imprinted genes exhibited intraspecific conservation, and these genes also exhibited interspecific conservation (rice, sorghum, and Arabidopsis) and were enriched in some specific pathways. By comparing intraspecific allelic DNA methylation in the endosperm, we found that nearly 15% of DNA methylation existed as allelic variants. The intraspecific whole-genome correlation between DNA methylation and imprinted genes indicated that DNA methylation variants play an important role in imprinting variants. Disruption of two conserved imprinted genes using CRISPR/Cas9 editing resulted in a smaller kernel phenotype. Our results shed light on the intraspecific correlation of DNA methylation variants and variation for imprinting in maize, and show that imprinted genes play an important role in kernel development. [ABSTRACT FROM AUTHOR]

Summary: Chlorella ohadii was isolated from desert biological soil crusts, one of the harshest habitats on Earth, and is emerging as an exciting new green model for studying growth, photosynthesis and metabolism under a wide range of conditions.Here, we compared the genome of C. ohadii, the fastest growing alga on record, to that of other green algae, to reveal the genomic imprints empowering its unparalleled growth rate and resistance to various stressors, including extreme illumination. This included the genome of its close relative, but slower growing and photodamage sensitive, C. sorokiniana UTEX 1663.A larger number of ribosome‐encoding genes, high intron abundance, increased codon bias and unique genes potentially involved in metabolic flexibility and resistance to photodamage are all consistent with the faster growth of C. ohadii. Some of these characteristics highlight general trends in Chlorophyta and Chlorella spp. evolution, and others open new broad avenues for mechanistic exploration of their relationship with growth.This work entails a unique case study for the genomic adaptations and costs of exceptionally fast growth and sheds light on the genomic signatures of fast growth in photosynthetic cells. It also provides an important resource for future studies leveraging the unique properties of C. ohadii for photosynthesis and stress response research alongside their utilization for synthetic biology and biotechnology aims. [ABSTRACT FROM AUTHOR]

Summary: We are becoming aware of a growing number of organisms that do not express genetic information equally from both parents as a result of an epigenetic phenomenon called genomic imprinting. Recently, it was shown that the entire paternal genome is repressed during the diploid phase of the life cycle of the liverwort Marchantia polymorpha. The deposition of the repressive epigenetic mark H3K27me3 on the male pronucleus is responsible for the imprinted state, which is reset by the end of meiosis. Here, we put these recent reports in perspective of other forms of imprinting and discuss the potential mechanisms of imprinting in bryophytes and the causes of its evolution. [ABSTRACT FROM AUTHOR]

Genomic imprinting is a specific mode of gene regulation which particularly accounts for the factors involved in development. Its disturbance affects the fetus, the course of pregnancy and even the health of the mother. In children, aberrant imprinting signatures are associated with imprinting disorders (ImpDis). These alterations also affect the function of the placenta, which has consequences for the course of the pregnancy. The molecular causes of ImpDis comprise changes at the DNA level and methylation disturbances (imprinting defects/ImpDefs), and there is an increasing number of reports of both pathogenic fetal and maternal DNA variants causing ImpDefs. These ImpDefs can be inherited, but prediction of the pregnancy complications caused is difficult, as they can cause miscarriages, aneuploidies, health issues for the mother and ImpDis in the child. Due to the complexity of imprinting regulation, each pregnancy or patient with suspected altered genomic imprinting requires a specific workup to identify the precise molecular cause and also careful clinical documentation. This review will cover the current knowledge on the molecular causes of aberrant imprinting signatures and illustrate the need to identify this basis as the prerequisite for personalized genetic and reproductive counselling of families. [ABSTRACT FROM AUTHOR]

PLAGL1 is one of a group of imprinted genes, whose altered expression causes imprinting disorders impacting growth, development, metabolism, and behavior. PLAGL1 over‐expression causes transient neonatal diabetes mellitus (TNDM type 1) and, based on murine models, under‐expression would be expected to cause growth restriction. However, only some reported individuals with upd(6)mat have growth restriction, giving rise to uncertainty about the role of PLAGL1 in human growth. Here we report three individuals investigated for growth restriction, two with upd(6)mat and one with a mosaic deletion of the paternally‐inherited allele of PLAGL1. These cases add to evidence of its involvement in pre‐ and early post‐natal human growth. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR), a leading cause of perinatal morbidity and mortality, is caused by fetal, maternal, and placental factors. Uniparental disomy (UPD) is a rare condition that leads to imprinting effects, low-level mosaic aneuploidies and homozygosity for pathogenic variants. In the present study, UPD events were detected in 5 women with FGR by trio exome sequencing (trio-WES) of a cohort of 150 FGR cases. Furthermore, noninvasive prenatal testing results of the 5 patients revealed a high risk of rare autosomal trisomy. Trio-WES showed no copy-number variations (CNVs) or nondisease-causing mutations associated with FGR. Among the 5 women with FGR, two showed gene imprinting, and two exhibited confined placental mosaicism (CPM) by copy number variant sequencing (CNV-seq). The present study showed that in FGR patients with UPD, the detection of imprinted genes and CPM could enhance the genetic diagnosis of FGR. [ABSTRACT FROM AUTHOR]

Some rare earth elements are occupational and environmental toxicants and can cause organ and systemic damage; therefore, they have attracted global attention. Neodymium oxide (Nd2O3) is a rare earth element that is refined and significantly utilized in China. The long noncoding RNA (lncRNA) H19 is encoded by the H19/IGF2 imprinted gene cluster located on human chromosome 11p15.5. H19 has become a research focus due to its ectopic expression leading to the promotion of fibrosis. However, the mechanisms by which it causes pulmonary fibrosis are elusive. This investigation indicates that biologically active Nd2O3 increases H19, SNIP1, and c-myc, decreases miR-29a-3p, accelerates macrophage M2 polarization, and causes pulmonary fibrosis in mice lung tissues. In macrophage-differentiated THP-1 cells, Nd2O3 (25 μg/ml) enhanced H19, SNIP1, and c-myc, reduced miR-29a-3p, accelerated macrophages M2 polarization, and stimulated fibrogenic cytokine (TGF-β1) secretion. Furthermore, the coculturing of Nd2O3-treated macrophage-differentiated THP-1 cells. And human embryonic lung fibroblast cells activated lung fibroblast, which increases the levels of collagen I, α-SMA, p-Smad2/3, and Smad4, whereas H19 knockdown or miR-29a-3p upregulation in macrophages had opposite effects. Moreover, it was revealed that H19/miR-29a-3p/SNIP1/c-myc regulatory axis is involved in pulmonary fibrosis induced by Nd2O3. Therefore, this study provides new molecular insights into the mechanism of pulmonary fibrosis by Nd2O3. [ABSTRACT FROM AUTHOR]