The DNA methylome and transcriptome of hyper-IgM syndrome type 2 B cells
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ABSTRACT:
PROVIDER: PRJNA721695 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14231328_1.fastq.gz | Fastqsanger.gz | |||
| SRR14231328_2.fastq.gz | Fastqsanger.gz | |||
| SRR14231329_1.fastq.gz | Fastqsanger.gz | |||
| SRR14231329_2.fastq.gz | Fastqsanger.gz | |||
| SRR14231330_1.fastq.gz | Fastqsanger.gz |
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Project description:Inactivating mutations in activation induced deaminase (AID) lead to hyper-IgM syndrome type 2 (HIGM2), a rare primary antibody deficiency. AID-mediated cytosine deamination has been proposed as mediating active demethylation, although there is evidence both to support and cast doubt on such a role. We here made use of HIGM2 B cells to investigate direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation defects. For genes that undergo demethylation in the transition from naïve to memory B cells but not in HIGM2 individuals, we did not observe AID involvement but a participation of TET enzymes. DNA methylation alterations in HIGM2 naïve B cells are related to premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data supports a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns without involvement of its cytosine deaminase activity.
2020-12-31 | GSE134664 | GEO
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2021-04-13 | GSE172012 | GEO
Project description:The DNA methylomes of hyper-IgM syndrome type 2 B cells provide insights into the roles of activation-induced deaminase prior to the germinal center reaction
| PRJNA556010 | ENA
Project description:BackgroundX-linked hyper-IgM (X-HIGM), which results from mutations in the CD40LG gene located on chromosome Xq26.3, is the most common form of HIGM. To date, more than 130 variants of the CD40L gene have been reported. We described a patient with novel de novo nuclear mitochondrial DNA sequences (NUMTs) in the CD40LG gene that have resulted in X-HIGM.MethodsWhole-exome sequencing (WES) analysis was used to screen for causal variants in the genome, and the candidate breakpoint was confirmed by Sanger sequencing.ResultsA new mutation of CD40LG, which deletes A at position 17 followed by a 147-nucleotide from mitochondrial DNA copies insertion in exon 1, was detected in a 20-month-old boy harbouring an X-HIGM combined with immunodeficiency syndrome.ConclusionThis is one of the few cases of a human genetic disease caused by nuclear mitochondrial DNA sequences (NUMTs). The presented data serve to demonstrate that de novo NUMT transfer of nucleic acid is a novel mechanism of X-HIGM.
| S-EPMC8172197 | biostudies-literature
Project description:Large/abnormal offspring syndrome (LOS/AOS) is a congenital overgrowth syndrome reported in ruminants produced by assisted reproduction (ART-LOS) which exhibit global disruption of the epigenome and transcriptome. LOS/AOS shares phenotypes and epigenotypes with the human congenital overgrowth condition Beckwith-Wiedemann syndrome. We have reported that LOS occurs spontaneously (SLOS), however, to date, no study has been conducted to determine if SLOS has the same methylome epimutations as ART-LOS. In this study, we performed whole genome bisulfite sequencing to examine global DNA methylation in SLOS and ART-LOS tissues. We observed unique patterns of global distribution of differentially methylated regions (DMRs) over different genomic contexts, such as promoters, CpG islands and surrounding regions, and repetitive sequences from different treatment groups. In addition, we identified hundreds of LOS-vulnerable DMRs across different cattle breeds when analyzing four idependent LOS experiments together. Specifically, there are 25 highly vulnerable DMRs that could potentially serve as molecular markers for the diagnosis of LOS, including at the promoters of DMRT2 and TBX18, at the imprinted gene bodies of IGF2R, PRDM8, and BLCAP/NNAT, and at multiple CpG islands. We also observed tissue-specific DNA methylation patterns between muscle and blood, and conservation of ART-induced DNA methylation changes between muscle and blood. We conclude that as in ART-LOS, alterations of the epigenome are involved in the etiology of SLOS. In addition, SLOS and ART-LOS share some similarities in methylome epimutations.
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| S-EPMC6030472 | biostudies-literature
Project description:PurposeThe United States Immunodeficiency Network (USIDNET) patient registry was used to characterize the presentation, genetics, phenotypes, and treatment of patients with Hyper IgM Syndrome (HIGM).MethodsThe USIDNET Registry was queried for HIGM patient data collected from October 1992 to July 2015. Data fields included demographics, criteria for diagnosis, pedigree analysis, mutations, clinical features, treatment and transplant records, laboratory findings, and mortality.ResultsFifty-two physicians entered data from 145 patients of ages 2 months to 62 years (median 12 years); 131 were males. Using patients' age at last entry, data from 2072 patient years are included. Mutations were recorded for 85 subjects; 82 were in CD40LG. Eighteen subjects had non-X-linked HIGM. 40 % had a normal serum IgM and 15 %, normal IgA. Infections were reported for 91 %, with pulmonary, ear, and sinus infections being the most common. 42 % had Pneumocystis jirovecii pneumonia; 6 % had Cryptosporidium. 41 % had neutropenia. 78 % experienced non-infectious complications: chronic diarrhea (n = 22), aphthous ulcers (n = 28), and neoplasms (n = 8) including colon cancer, adrenal adenoma, liver adenocarcinoma, pancreatic carcinoid, acute myeloid leukemia, hepatoma, and, in a female with an autosomal dominant gain of function mutation in PIK3CD, an ovarian dysgerminoma. Thirteen patients had a hematopoietic marrow or stem cell transplant; three had solid organ transplants. Thirteen were known to have died (median age = 14 years).ConclusionsAnalysis of the USIDNET Registry provides data on the common clinical features of this rare syndrome, and in contrast with previously published data, demonstrates longer survival times and reduced gastrointestinal manifestations.
| S-EPMC5039943 | biostudies-literature
Project description:Innate immune memory, also refered to as trained immunity (TRIM) is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components. In this study we performed epigenomic and transcriptomic analysis of HIDS (Hyper IgD Syndrome) patients at baseline, and after 24 hours culture in media (RPMI only) or media + 10ng/mL LPS. HIDS is associated with the accumulation of mevalonate, a monocyte trainer.
2018-01-08 | GSE104282 | GEO
Project description:Assisted reproductive therapies (ART) have become increasingly common worldwide and up to ~6% of children currently born in developed countries were conceived employing these technologies. Numerous retrospective studies have suggested that ART-conceived children are more likely to develop the overgrowth syndrome Beckwith-Wiedemann (BWS). In bovine, the use of ART can induce a similar overgrown condition, which is referred to as large offspring syndrome (LOS). Both BWS and LOS involve dysregulation of imprinted genes. However, it remains largely unknown whether aberrant gene expression and DNA methylation occur at non-imprinted loci and to what extent these molecular alterations can contribute to these syndromes. Here we examined the transcriptome of skeletal muscle, liver, kidney, and brain of control and LOS bovine fetuses and found that different LOS fetuses exhibit different severity of the transcriptome alterations and different tissues have distinct gene pathways disturbed in LOS fetuses. Particularly for skeletal muscle, multiple pathways involved in myoblast proliferation and fusion into myotubes are misregulated in LOS fetuses. Further, characterization of the methylome of skeletal muscle demonstrates numerous local methylation differences; however, global DNA methylation is comparable between all individuals regardless of bodyweight. Importantly, only a small percent of differentially expressed genes (DEGs) including the imprinted gene IGF2R can be linked to the neighboring differentially methylated regions (DMRs). In summary, we not only show that misregulation of non-imprinted genes in addition to loss-of-imprinting contributes to the ART-induced overgrowth syndrome but also demonstrate that most of the aberrant gene expression is not associated with DNA methylome epimutations.
2017-10-31 | GSE93775 | GEO