Histone methyltransferase DOT1L is essential for self-renewal of germline stem cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA796616 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19214118.fastq.gz | Fastqsanger.gz | |||
| SRR19214119.fastq.gz | Fastqsanger.gz | |||
| SRR19214120.fastq.gz | Fastqsanger.gz | |||
| SRR19214121.fastq.gz | Fastqsanger.gz | |||
| SRR19214122.fastq.gz | Fastqsanger.gz |
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Project description:Spermatogonial stem cells undergo both self-renewal to maintain the stem cell population and differentiation to produce mature sperm. These processes are controlled by both stem cell-intrinsic and external niche factors. DOT1L, the sole H3K79 methyltransferase, is dispensable for mouse embryonic stem cell self-renewal but instead functions as a barrier to somatic cell reprogramming. Here we show that DOT1L is required for spermatogonial stem cell self-renewal. Mice lacking DOT1L in the germ cells show a failure in the maintenance of spermatogonial stem cells without a block in spermatogenic cell differentiation and thus a progressive loss of germ cells, leading to a Sertoli-cell-only syndrome. Chemical inhibition of DOT1L in cultured stem cells reduces the spermatogonial stem cell activity after transplantation. RNA-seq analysis reveals downregulation of Hoxc cluster genes in DOT1L-inhibited spermatogonia stem cells. Single cell RNA-seq analysis demonstrates that inhibition of DOT1L sequesters spermatogonial stem cells in a primitive state and prevents them from transitioning to a progenitor state. These results identify a new function for DOT1L in adult stem cells and provides a paradigm for regulation of spermatogonial stem cell self-renewal. Self-renewal of spermatogonial stem cells is vital to life-long production of male gametes and thus fertility. However, the underlying mechanisms remain enigmatic. Here, we show that DOT1L, the sole H3K79 methyltransferase, is required for spermatogonial stem cell self-renewal. Mice lacking DOT1L fail to maintain spermatogonial stem cells, characterized by a sequential loss of germ cells from spermatogonia to spermatids and ultimately a Sertoli-cell-only syndrome. Inhibition of DOT1L reduces the stem cell activity after transplantation, prevents spermatogonial stem cells from transitioning to a progenitor state, and sequesters them in a primitive state. Furthermore, DOT1L promotes expression of the fate-determining HoxC transcription factors in spermatogonial stem cells. Our findings identify an essential function for DOT1L in adult stem cells and provide an epigenetic paradigm for regulation of spermatogonial stem cells.
2022-06-30 | GSE193575 | GEO
Project description:Acute myelogenous leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the mechanism underpinning the enhanced self-renewal conferred by cohesin haploinsufficiency. Using primary (HSPCs) as a model we demonstrate that a reduction in a core cohesin subunit is associated with decreased H3K27me3 and increased H3K79me2, along with increased self-renewal capacity and a leukemic transcriptional profile. Inhibition of DOT1L in cohesin-depleted HSPCs restored normal self-renewal, H3K27me3 and H3K79me2 levels, and gene expression, identifying DOT1L as a potential therapeutic target in cohesin haploinsufficient AML. Together our data further characterizes the mechanism by which cohesin mutations contribute to AML and identifies DOT1L as a potential therapeutic target for AML patients harboring cohesin mutations.
2021-02-25 | GSE140359 | GEO
Project description:Acute myelogenous leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the mechanism underpinning the enhanced self-renewal conferred by cohesin haploinsufficiency. Using primary (HSPCs) as a model we demonstrate that a reduction in a core cohesin subunit is associated with decreased H3K27me3 and increased H3K79me2, along with increased self-renewal capacity and a leukemic transcriptional profile. Inhibition of DOT1L in cohesin-depleted HSPCs restored normal self-renewal, H3K27me3 and H3K79me2 levels, and gene expression, identifying DOT1L as a potential therapeutic target in cohesin haploinsufficient AML. Together our data further characterizes the mechanism by which cohesin mutations contribute to AML and identifies DOT1L as a potential therapeutic target for AML patients harboring cohesin mutations.
2021-02-25 | GSE140360 | GEO
Project description:DOT1L inhibitors block abnormal self-renewal induced by cohesin loss
| PRJNA589333 | ENA
Project description:Self-renewal of spermatogonial stem cells is vital to lifelong production of male gametes and thus fertility. However, the underlying mechanisms remain enigmatic. Here, we show that DOT1L, the sole H3K79 methyltransferase, is required for spermatogonial stem cell self-renewal. Mice lacking DOT1L fail to maintain spermatogonial stem cells, characterized by a sequential loss of germ cells from spermatogonia to spermatids and ultimately a Sertoli cell only syndrome. Inhibition of DOT1L reduces the stem cell activity after transplantation. DOT1L promotes expression of the fate-determining HoxC transcription factors in spermatogonial stem cells. Furthermore, H3K79me2 accumulates at HoxC9 and HoxC10 genes. Our findings identify an essential function for DOT1L in adult stem cells and provide an epigenetic paradigm for regulation of spermatogonial stem cells.
| S-EPMC9296001 | biostudies-literature
Project description:DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [RNA-seq]
| PRJNA589334 | ENA
Project description:DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [ChIP-seq]
| PRJNA589335 | ENA
Project description:Purpose: Piwi family protein Aubergine (Aub) maintains genome integrity in late germ cells of the Drosophila ovary through piRNA-mediated repression of transposon activities. Although it is highly expressed in germline stem cells (GSCs) and early progeny, it remains unclear if it plays any roles in early GSC lineage development. Results: The study reveals a novel function of Aub in GSCs and their progeny, which promotes translation of self-renewal and differentiation factors by directly binding to its target mRNAs and interacting with translational initiation factors.
2017-04-01 | GSE96751 | GEO
Project description:Cell lines geneticially engineered to undergo conditional asymmetric self-renewal were used to identify genes whose expression is asymmetric self-renewal associated (ASRA). Non-random sister chromatid segregation occurs concordantly with asymmetric self-renewal in these cell lines. Asymmetric self-renewal occurs when murine embryo fibroblasts that are otherwise p53-null are induced to express physiological levels of wildtype p53 protein (Asym). To distinguish p53-responsive genes that also require induction of asymmetric self renewal (i.e., ASRA genes) and/or non-random sister chromatid segregation for change, an additional control cell line, which continues to symmetrically self-renew (with random sister chromatid segregation) even when p53 is induced, was also compared (Symp53). This congenic cell line constitutively expresses the type II inosine monophosphate dehydrogenase (IMPDH II; the rate-limiting enzmye for guanine ribonucleotide biosynthesis) and, thereby, prevents p53-induced asymmetric self-renewal and non-random sister chromatid segregation. Three biological replicates of asymmetrically self-renewing cultures (Asym1-3) were compared with cultures that were symmetrically self-renewing - either because they did not express p53 (3 biological replicates, Sym1-3) or they expressed constitutive IMPDH II (i.e., not regulated by p53) as well as p53 (2 biological replicates, Symp53_1 and 2.)
2010-12-22 | E-GEOD-25334 | biostudies-arrayexpress
Project description:Insights into the epigenetic mechanisms of CD8 T cell differentiation are delivering novel opportunities for modulating fate decisions and immune responses. The histone methyltransferase DOT1L is emerging as central epigenetic regulator in immune cells. However, its cell-intrinsic role in CD8 T cell programming remains unclear as positive as well as negative roles have been ascribed to DOT1L. Here, we determined the cell-intrinsic role of DOT1L in CD8 T cells using conditional ablation. In contrast to deletion of Dot1L early in the T cell lineage, conditional ablation of Dot1L in isolated mature CD8 T cells in vitro did not compromise the in vivo proliferative capacity and anti-tumor reactivity. In vitro, Dot1L knock-out CD8 T cells showed accelerated and enhanced antigen-specific cytotoxic activity towards tumor cells. Mechanistically, transcriptome and proteome profiling revealed that loss of DOT1L results in an altered cell-identity program with loss of T-cell and gain of NK-cell features. This role of DOT1L was linked to its catalytic activity since treatment with specific DOT1L inhibitors phenocopied genetic deletion of Dot1L. Our findings show that ablation of DOT1L activity is well-tolerated in mature CD8 T cells, rewires their cell identity in a tunable way towards the NK-cell lineage and enhances their cytolytic activity cell intrinsically. Highlights • Differentiation and identity of cytotoxic T cells critically depend on the methyltransferase DOT1L • DOT1L limits the cytotoxic activity of mature CD8 T cells • DOT1 prohibits the acquisition of NK cell features in CD8 T cells • DOT1L maintains CD8 T cell identity through its catalytic activity in a dose-dependent manner
2025-11-10 | PXD057606 | Pride