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Amplicon-seq of SVA methylation in human sperm

ABSTRACT: DNA methylation, repressive histone modifications, and PIWI-interacting RNA are essential for controlling retroelement silencing in the mammalian germ line. Dysregulation of retroelement silencing is associated with male sterility. Although DNA methylation mechanisms have been extensively studied in mouse germ cells, little progress has been made in humans. Here, we show that the Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs) are associated with DNA methylation of retroelements in human primordial germ cells (hPGCs), and hominoid-specific retroelement SINE-VNTR-Alus (SVA) is subjected to transcription-directed de novo DNA methylation during human spermatogenesis. Furthermore, we show that the degree of de novo DNA methylation in SVAs varies among human individuals, which confers a major inter-individual epigenetic variation in sperm. Collectively, our results provide potential molecular mechanisms of how retroelements are regulated during human male germ cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE174562 | GEO | 2021/08/01

REPOSITORIES: GEO

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Mini-heterochromatin domains constrain the cis-regulatory impact of SVA transposons in human brain development and disease

Project description:SVA retrotransposons remain active in humans and contribute to individual genetic variation. Polymorphic SVA alleles harbor gene-regulatory potential and can cause genetic disease. However, how SVA insertions are controlled and functionally impact human disease is unknown. Here, we dissect the epigenetic regulation and influence of SVAs in cellular models of X-linked dystonia-parkinsonism (XDP), a neurodegenerative disorder caused by an SVA insertion at the TAF1 locus. We demonstrate that the KRAB zinc finger protein ZNF91 establishes H3K9me3 and DNA methylation over SVAs, including polymorphic alleles, in human neural progenitor cells. The resulting mini-heterochromatin domains attenuate the cis-regulatory impact of SVAs. This is critical for XDP pathology; removal of local heterochromatin severely aggravates the XDP molecular phenotype, resulting in increased TAF1 intron retention and reduced expression. Our results provide unique mechanistic insights into how human polymorphic transposon insertions are recognized, and their regulatory impact constrained by an innate epigenetic defense system.

2023-11-01 | GSE245093 | GEO

Specific genomic features underlie the co-option of SVA transposons as cis-regulatory elements in the human genome

Project description:Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, why some TEs are co-opted as functional enhancers while others are not is underappreciated. SINE-Vntr-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-exclusive. Many studies indicated that the SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such process have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication into human stem-cell gene regulation. We found that ~750 SVAs are co-opted as functional cis-regulatory elements in human induced Pluripotent Stem Cells. Co-opted SVAs are significantly closer to genes and harbor more transcription factor binding sites than the not co-opted ones. We show that a long DNA-motif composed of flanking YY1/2 and OCT4 binding sites is enriched in the co-opted SVAs, and that these two factors bind, as predicted, near each other on the TE sequence. Repression of all the ~750 co-opted SVAs by CRISPRi in a line with stem-like properties (NCCIT) led to loss of YY1/OCT4 binding and alteration of neighboring gene expression. Ultimately, SVA repression resulted in ~3,000 differentially expressed genes, 131 of which were the nearest gene to an annotated SVA. In summary, we demonstrated that SVAs contribute significantly to human gene regulation, and that both genomic location and sequence composition contribute to SVA domestication in the gene regulatory networks.

2022-01-04 | GSE192951 | GEO

Demethylation and derepression of genomic retroelements in the skeletal muscles of aged mice

Project description:Changes in DNA methylation influence the aging process and contribute to aging phenotypes, but few studies have been conducted on DNA methylation changes in conjunction with skeletal muscle aging. We explored the DNA methylation changes in a variety of retroelement families throughout aging (at 2, 20, and 28 months of age) in murine skeletal muscles by methyl-binding domain sequencing (MBD-seq). The two following contrasting patterns were observed among the members of each repeat family in superaged mice: (1) hypermethylation in weakly methylated retroelement copies and (2) hypomethylation in copies with relatively stronger methylation levels, representing a pattern of “regression toward the mean” within a single retroelement family. Interestingly, these patterns depended on the sizes of the copies. While the majority of the elements showed a slight increase in methylation, the larger copies (>5 kb) displayed evident demethylation. All these changes were not observed in T cells. RNA sequencing revealed a global derepression of retroelements during the late phase of aging (between 20-28 months of age), which temporally coincided with retroelement demethylation. Following this methylation drift trend of “regression toward the mean”, aging tended to progressively lose the preexisting methylation differences and local patterns in the genomic regions that had been elaborately established during the early period of development.

2019-09-16 | GSE123954 | GEO

The dynamic reprogramming of H3K9me3 at hominoid-specific retrotransposons during early human development

Project description:Reprogramming of H3K9me3-dependent heterochromatin is required for early development. How H3K9me3 is involved in early human development is, however, largely unclear. Here, we resolve the temporal landscape of H3K9me3 during human preimplantation development and its regulation for diverse hominoid-specific retrotransposons. At the 8-cell stage, H3K9me3 reprogramming at hominoid-specific retrotransposons termed SINE-VNTR-Alu (SVA) facilitates interaction between certain promoters and SVA-derived enhancers, facilitating the zygotic genome activation. In trophectoderm, de novo H3K9me3 domains prohibit pluripotent transcription factors from binding on hominoid-specific retrotransposons-derived regulatory elements for inner cell mass (ICM)-specific genes. H3K9me3 re-establishment at SVA elements in ICM is associated with higher transcription of DNA damage repair genes, compared to naïve human pluripotent stem cells. Our data demonstrate that species-specific reorganization of H3K9me3-dependent heterochromatin at hominoid-specific retrotransposons plays important roles during early human development, shedding light on how the epigenetic regulatory network for early development has evolved in mammals.

2022-07-14 | GSE176016 | GEO

Default DNA Methylation is Preceded by Broad, Low-Level Transcription in Fetal Male Germ Cells and Is Inversely Patterned by Dynamic H3K4 Methylation (ChIP-chip and MIRA-chip)

Project description:To understand what dictates the emerging patterns of de novo DNA methylation, we mapped DNA methylation, chromatin, and transcription changes in purified fetal mouse germ cells using MIRA-chip, ChIP-chip, and strand-specific RNA-seq, respectively. De novo methylation occurred without any apparent trigger from preexisting repressing chromatin marks but was preceded by broad, low-level transcription along the entire genome in prospermatogonia. Only distinct short sequences remained unmethylated, precisely aligned with constitutive or emerging peaks of H3K4me2. Establishment of methylation at differentially methylated regions (DMRs) of imprinted genes, CpG islands, and IAPs followed these same default rules. Transcription run-through occurred at paternal DMRs with no- or diminishing H3K4me2 peaks. Maternal DMRs remained unmethylated among highly methylated DNA at precisely aligned H3K4me2 peaks with transcription initiating at least in one strand. Our results suggest that the pattern of de novo DNA methylation in prospermatogonia is dictated by opposing actions of broad, low-level transcription and dynamic patterns of active chromatin. ChIP-chip and MIRA-chip were performed to map histone modifications and DNA methylation at different devlopmental time points in germ cells and somatic cells along known imprinted domains and control regions, using custom NimbleGen tiling arrays.

2013-07-31 | E-GEOD-45836 | biostudies-arrayexpress

Default DNA Methylation is Preceded by Broad, Low-Level Transcription in Fetal Male Germ Cells and Is Inversely Patterned by Dynamic H3K4 Methylation (RNA-Seq)

Project description:To understand what dictates the emerging patterns of de novo DNA methylation, we mapped DNA methylation, chromatin, and transcription changes in purified fetal mouse germ cells using MIRA-chip, ChIP-chip, and strand-specific RNA-seq, respectively. De novo methylation occurred without any apparent trigger from preexisting repressing chromatin marks but was preceded by broad, low-level transcription along the entire genome in prospermatogonia. Only distinct short sequences remained unmethylated, precisely aligned with constitutive or emerging peaks of H3K4me2. Establishment of methylation at differentially methylated regions (DMRs) of imprinted genes, CpG islands, and IAPs followed these same default rules. Transcription run-through occurred at paternal DMRs with no- or diminishing H3K4me2 peaks. Maternal DMRs remained unmethylated among highly methylated DNA at precisely aligned H3K4me2 peaks with transcription initiating at least in one strand. Our results suggest that the pattern of de novo DNA methylation in prospermatogonia is dictated by opposing actions of broad, low-level transcription and dynamic patterns of active chromatin. Strand-specific RNA-seq was done in male and female fetal germ cells and somatic gonadal cells at 15.5 dpc to map transcription.

2013-07-31 | E-GEOD-46953 | biostudies-arrayexpress

Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

Project description:Reverse transcription-derived sequences account for at least half of the human genome. Although these retroelements are formidable motors of evolution, they can occasionally cause disease, and accordingly are inactivated during early embryogenesis through epigenetic mechanisms. In the mouse, at least for endogenous retroviruses, important mediators of this process are the tetrapod-specific KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor TRIM28. The present study demonstrates that KRAB/TRIM28-mediated regulation is responsible for controlling a very broad range of human-specific endogenous retroelements (EREs) in human embryonic stem (ES) cells and that it exerts, as a consequence, a marked effect on the transcriptional dynamics of these cells. It further reveals reciprocal dependence between TRIM28 recruitment at specific families of EREs and DNA methylation. It finally points to the importance of persistent TRIM28-mediated control of ERE transcriptional impact beyond their presumed inactivation by DNA methylation. Analyses of epigentic effectors and marks in KAP1 WT and KD human embryonic stem cells

2014-05-29 | E-GEOD-57989 | biostudies-arrayexpress

Lineage-specific functions of TET1 in the post-implantation mouse embryo.: RNA-Seq of in vitro converted primed epiblast-like cells

Project description:The mammalian TET dioxygenases contribute to global waves of DNA demethylation in the zygote and in primordial germ cells, but their involvement during de novo DNA methylation at peri/post-implantation development is unknown. Here, we investigate the role

2017-05-15 | E-MTAB-4578 | biostudies-arrayexpress

Homo sapiens

Project description:Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

| PRJNA248665 | ENA

C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germline

Project description:In the male mouse germline, PIWI-interacting RNAs (piRNAs), bound by the PIWI protein MIWI2 (PIWIL4), guide the DNA methylation of young active transposable elements (TEs) through SPOCD1. We identified loss-of-function variants in human SPOCD1 that cause male infertility and defective TE silencing. One SPOCD1 pathogenic allele encodes a truncated protein that lacks the conserved carboxy-terminus. We demonstrated that this deleted region interacts with C19ORF84. In mouse foetal germ cells, the nuclear protein C19ORF84 is required for the association of SPOCD1 with DNMT3L, an essential component of the de novo methylation machinery. In summary, we identified a conserved role for SPOCD1 in safeguarding the continuity of the human germline and discovered C19ORF84, an uncharacterised protein essential for 15 orchestrating piRNA-directed DNA methylation.

2024-02-13 | E-MTAB-11612 | biostudies-arrayexpress

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