DNA methylation in mammalian development and disease

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 12, 2024

The DNA methylation field has matured from a phase of discovery and genomic characterization to one seeking deeper functional understanding how this modification contributes development, ageing disease. In particular, the past decade seen many exciting mechanistic discoveries that have substantially expanded our appreciation for generic, evolutionarily ancient can be incorporated into robust epigenetic codes. Here, we summarize current distinct landscapes emerge over mammalian lifespan discuss they interact with other regulatory layers support diverse functions. We then review rising interest in alternative patterns found during senescence somatic transition cancer. Alongside advancements single-cell long-read sequencing technologies, collective insights made across these fields offer new opportunities connect biochemical genetic features cell physiology, developmental potential phenotype. Review, Smith et al. describe development within key disease states, as well different methyltransferases interface histone modifications proteins create maintain them.

Language: Английский

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3D reconstruction of a gastrulating human embryo

Cell, Journal Year: 2024, Volume and Issue: 187(11), P. 2855 - 2874.e19

Published: April 23, 2024

Language: Английский

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Efficient differentiation of human primordial germ cells through geometric control reveals a key role for Nodal signaling

eLife, Journal Year: 2022, Volume and Issue: 11

Published: April 8, 2022

Human primordial germ cells (hPGCs) form around the time of implantation and are precursors eggs sperm. Many aspects hPGC specification remain poorly understood because inaccessibility early postimplantation human embryo for study. Here, we show that micropatterned pluripotent stem (hPSCs) treated with BMP4 give rise to hPGC-like (hPGCLC) use these as a quantitatively reproducible simple in vitro model interrogate this important developmental event. We characterize hPSCs up 96 hr hPGCLC populations stable continue mature. By perturbing signaling during differentiation, identify previously unappreciated role Nodal find relative timing duration BMP critical parameters controlling number hPGCLCs. formulate mathematical network cross-repressive fates driven by signaling, which predicts measured fate patterns after perturbations. Finally, hPSC colony size dictates efficiency specification, led us dramatically improve differentiation.

Language: Английский

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A paternal bias in germline mutation is widespread in amniotes and can arise independently of cell division numbers

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Aug. 2, 2022

In humans and other mammals, germline mutations are more likely to arise in fathers than mothers. Although this sex bias has long been attributed DNA replication errors spermatogenesis, recent evidence from points the importance of mutagenic processes that do not depend on cell division, calling into question our understanding basic phenomenon. Here, we infer ratio paternal-to-maternal mutations,

Language: Английский

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Understanding testicular single cell transcriptional atlas: from developmental complications to male infertility

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 15

Published: July 11, 2024

Spermatogenesis is a multi-step biological process where mitotically active diploid (2n) spermatogonia differentiate into haploid (n) spermatozoa via regulated meiotic programming. The alarming rise in male infertility has become global concern during the past decade thereby demanding an extensive profiling of testicular gene expression. Advancements Next-Generation Sequencing (NGS) technologies have revolutionized our empathy towards complex events including spermatogenesis. However, despite multiple attempts made to reveal transcriptional signature(s) either with bulk tissues or at single-cell, level, comprehensive reviews on transcriptomics and associated disorders are limited. Notably, explicating genome-wide expression patterns various stages spermatogenic progression provide dynamic molecular landscape transcription. Our review discusses advantages single-cell RNA-sequencing (Sc-RNA-seq) over RNA-seq concerning tissues. Additionally, we highlight cellular heterogeneity, spatial transcriptomics, cell-to-cell interactions distinct cell populations within testes germ cells (Gc), Sertoli (Sc), Peritubular (PTc), Leydig (Lc), etc. Furthermore, summary key finding transcriptomic studies that shed light developmental mechanisms implicated infertility. These insights emphasize pivotal roles Sc-RNA-seq advancing knowledge regarding may serve as potential resource formulate future clinical interventions for reproductive health.

Language: Английский

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Effects of Gonadotropin‐Releasing Hormone Analogues on Ovarian Function and Embryogenesis: A Cyclophosphamide‐Induced Mouse Model Study

BJOG An International Journal of Obstetrics & Gynaecology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

ABSTRACT Objective To clarify the protective effects of gonadotropin‐releasing hormone analogues (GnRHas) on cyclophosphamide (CTX)‐induced oocyte number loss and development potential damage. Design Mice model study. Setting Laboratory‐based animal study conducted in controlled research facilities. Population Female C57/BL6 mice subjected to CTX‐induced ovarian Methods The GnRHa CTX were evaluated terms hormones, count slices, established three‐dimensional–constructed ovaries, vitro fertilisation, RNA sequencing microinjection. Main Outcome Measures main outcome measures oocytes intact mouse ovaries quality, using three‐dimensional (3D) tissue‐clearing methods, oxidative stress markers (reactive oxygen species [ROS] malondialdehyde [MDT]), mitochondrial function (ATP levels), embryogenesis rates at two‐cell, four‐cell blastocyst stages. Results In mice, pretreatment did not protect endocrine changes, but protected slice counting. A technique, CUBIC (Clear, Unobstructed Body Imaging Cocktails), was a suitable method for clearing, 3D counting validated with accuracy 105.22% ± 3.48%. By this method, also found (597 28 vs. 222 15, p < 0.0001), which may be mediated by upregulated anti‐Müllerian (AMH) levels inhibiting primordial follicle approved culture ovaries. increased retrieved (19.4 2.1 15.0 1.6, 0.0001) developmental ability (65.0 4.6 48.1 4.2 blastocyst, 0.0001). revealed downregulated pathways exogenous drug metabolism, cytochrome P450, detection adenosine triphosphate (ATP), MDA ROS levels. up‐expression Cox17 (cytochrome c oxidase copper chaperone 17) after confirmed PCR microinjection si from mice. Conclusions associated reduced improved embryogenesis, likely AMH upregulation.

Language: Английский

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Single-nucleus multiomics reveals the gene regulatory networks underlying sex determination of murine primordial germ cells

eLife, Journal Year: 2025, Volume and Issue: 13

Published: March 10, 2025

Accurate specification of female and male germ cells during embryonic development is critical for sexual reproduction. Primordial (PGCs) are the bipotential precursors mature gametes that commit to an oogenic or spermatogenic fate in response sex-determining cues from fetal gonad. The processes required PGCs integrate respond signals somatic environment gonads not well understood. In this study, we developed first single-nucleus multiomics map chromatin accessibility gene expression murine PGC both XX XY embryos. Profiling cell-type-specific transcriptomes regions open same cell captured molecular signatures networks underlying sex determination. Joint RNA ATAC data single resolved previously unreported subpopulations cataloged a multimodal reference atlas differentiating clusters. We discovered regulatory element precedes development, suggesting changes may prime lineage commitment prior differentiation. Similarly, found dimorphism increased temporally PGCs. Combining sequencing data, computationally mapped cohort transcription factors regulate sexually dimorphic genes For example, enriched factors, TFAP2c, TCFL5, GATA2, MGA, NR6A1, TBX4, ZFX. Sex-specific enrichment forkhead-box POU6 families was also observed Finally, determined temporal patterns WNT, BMP, RA signaling determination, our discovery analyses identified potentially new communication pathways between supporting Our results illustrate diversity involved programming toward sex-specific fate.

Language: Английский

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Germline stem cells in human

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Oct. 2, 2022

Abstract The germline cells are essential for the propagation of human beings, thus survival mankind. stem cells, as a unique cell type, generate various states germ and then differentiate into specialized spermatozoa ova, producing offspring, while self-renew to more cells. Abnormal development often causes severe diseases in humans, including infertility cancer. Primordial (PGCs) first emerge during early embryonic development, migrate gentile ridge, join formation gonads. In males, they spermatogonial which give rise via meiosis from onset puberty, females, female (FGSCs) retain stemness ovary initiate oocytes. cell-like (PGCLCs) can be induced vitro or pluripotent this review, we focus on current advances these adult PGCLCs provide an overview molecular mechanisms underlying differentiation outline their physiological functions, pathological implications, clinical applications.

Language: Английский

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Human reproduction is regulated by retrotransposons derived from ancient Hominidae-specific viral infections

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Jan. 24, 2022

Germ cells are essential to pass DNA from one generation the next. In human reproduction, germ cell development begins with specification of primordial (PGCs) and a failure specify PGCs leads infertility. Recent studies have revealed that transcription factor network required for PGC has diverged in mammals, this significant impact on our understanding reproduction. Here, we reveal Hominidae-specific Transposable Elements (TEs) LTR5Hs, may serve as TEENhancers (TE Embedded eNhancers) facilitate specification. LTR5Hs become transcriptionally active during both vivo vitro epigenetic reprogramming leading increased chromatin accessibility, localized demethylation, enrichment H3K27ac, occupation key hPGC factors. Inactivation KRAB mediated CRISPRi summary, data reveals role development.

Language: Английский

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Transgene-Free Ex Utero Derivation of A Human Post-Implantation Embryo Model Solely from Genetically Unmodified Naïve PSCs

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 15, 2023

Abstract Our ability to study early human post-implantation development remains highly limited due the ethical and technical challenges associated with intrauterine of embryo after implantation. Despite great progress made on gastruloids, axioloids in vitro cultured blastoids, such elegant models do not constitute an integrated Stem cell-derived Embryo Models (SEMs) that includes all key extra-embryonic tissues conceptus (e.g., hypoblast, yolk-sac, trophoblasts, amnion, extraembryonic mesoderm), thus, recapitulate epiblast within context these compartments. Mouse naïve pluripotent stem cells (PSCs) have recently been shown give rise embryonic capable self-assembling into post-gastrulation mouse SEMs, while bypassing blastocyst-like stage, eventually initiating organogenesis ex utero . Here, we implement critical adaptations extend finding humans, using only genetically unmodified PSCs, thus circumventing need for ectopic expression lineage promoting transgenes. Such SEMs organization known compartments stage embryos, including epiblast, mesoderm, trophoblast surrounding latter layers. The organized hallmarks embryogenesis up 13-14 days post-fertilization (dpf, Carnegie 6a), as bilaminar disk formation, lumenogenesis, amniogenesis, anterior-posterior symmetry breaking, PGC specification, primary secondary yolk sac mesoderm expansion defines a chorionic cavity connective stalk. This new platform constitutes tractable cell-based model experimentally interrogating previously inaccessible windows peri- development.

Language: Английский

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