DMRT1-mediated reprogramming drives development of cancer resembling human germ cell tumors with features of totipotency
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA628924 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11625100.fastq.gz | Fastqsanger.gz | |||
| SRR11625101.fastq.gz | Fastqsanger.gz | |||
| SRR11625102.fastq.gz | Fastqsanger.gz | |||
| SRR11625103.fastq.gz | Fastqsanger.gz | |||
| SRR11625104.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 84 |
Similar Datasets
Project description:In vivo reprogramming provokes a wide range of cell fate conversion. Here, we discover that in vivo induction of higher levels of OSKM in mouse somatic cells leads to increased expression of primordial germ cell (PGC)-related genes and provokes genome-wide erasure of genomic imprinting, which takes place exclusively in PGCs. Moreover, the in vivo OSKM reprogramming results in development of cancer that resembles human germ cell tumors. Like a subgroup of germ cell tumors, propagated tumor cells differentiate into trophoblasts. Moreover, these tumor cells give rise to induced pluripotent stem cells (iPSCs) with expanded differentiation potential into trophoblasts. Remarkably, the tumor-derived iPSCs are able to contribute to non-neoplastic somatic cells in adult mice. Mechanistically, DMRT1, which is expressed in PGCs, drives the reprogramming and propagation of the tumor cells in vivo. Furthermore, the DMRT1-related epigenetic landscape is associated with trophoblast competence of the reprogrammed cells and provides a therapeutic target for germ cell tumors. These results reveal an unappreciated route for somatic cell reprogramming and underscore the impact of reprogramming in development of germ cell tumors.
2021-07-20 | GSE149499 | GEO
Project description:In vivo reprogramming provokes a wide range of cell fate conversion. Here, we discover that in vivo induction of higher levels of OSKM in mouse somatic cells leads to increased expression of primordial germ cell (PGC)-related genes and provokes genome-wide erasure of genomic imprinting, which takes place exclusively in PGCs. Moreover, the in vivo OSKM reprogramming results in development of cancer that resembles human germ cell tumors. Like a subgroup of germ cell tumors, propagated tumor cells can differentiate into trophoblasts. Moreover, these tumor cells give rise to induced pluripotent stem cells (iPSCs) with expanded differentiation potential into trophoblasts. Remarkably, the tumor-derived iPSCs are able to contribute to non-neoplastic somatic cells in adult mice. Mechanistically, DMRT1, which is expressed in PGCs, drives the reprogramming and propagation of the tumor cells in vivo. Furthermore, the DMRT1-related epigenetic landscape is associated with trophoblast competence of the reprogrammed cells and provides a therapeutic target for germ cell tumors. These results reveal an unappreciated route for somatic cell reprogramming and underscore the impact of reprogramming in development of germ cell tumors.
| S-EPMC8377058 | biostudies-literature
Project description:Transcription factors related to the insect sex determination gene Doublesex (DMRT proteins) control sex determination and/or sexual differentiation in diverse metazoans. They also are implicated in transitions between sex-determining mechanisms during vertebrate evolution. In mice Dmrt1 is required for male gonadal differentiation in somatic cells and germ cells. DMRT1 also maintains male gonadal sex: its loss, even in adults, can trigger sexual fate reprogramming in which male Sertoli cells transdifferentiate into their female equivalents - granulosa cells - and testicular tissue reorganizes to a more ovarian morphology. Here we use a conditional Dmrt1 transgene to show that Dmrt1 is not only necessary but also sufficient to specify male cell identity in the mouse gonad. DMRT1 expression in the ovary silenced the female sex-maintenance gene Foxl2 and reprogrammed juvenile and adult granulosa cells into Sertoli-like cells, triggering formation of structures resembling male seminiferous tubules. DMRT1 can silence Foxl2 even in the absence of the testis-determining genes Sox8 and Sox9. mRNA profiling found that DMRT1 activates many testicular genes and downregulates ovarian genes and single cell RNA-seq in transdifferentiating cells identified dynamically expressed candidate mediators of this process. Strongly upregulated genes were highly enriched on chromosome X, consistent with sexually antagonistic functions. This study provides an in vivo example of single gene reprogramming of cell sexual identity. Our findings suggest a reconsideration of mechanisms involved in human disorders of sexual development (DSD) and empirically support evolutionary models where loss or gain of Dmrt1 function promotes establishment of new vertebrate sex determination systems. RNA-Seq (3 conditions, 2 replicates per condition) and Single Cell RNA-Seq (68 individual cells and 1 bulk cell sample)
2015-02-27 | E-GEOD-64960 | biostudies-arrayexpress
Project description:Transcription factors related to the insect sex determination gene Doublesex (DMRT proteins) control sex determination and/or sexual differentiation in diverse metazoans. They also are implicated in transitions between sex-determining mechanisms during vertebrate evolution. In mice Dmrt1 is required for male gonadal differentiation in somatic cells and germ cells. DMRT1 also maintains male gonadal sex: its loss, even in adults, can trigger sexual fate reprogramming in which male Sertoli cells transdifferentiate into their female equivalents - granulosa cells - and testicular tissue reorganizes to a more ovarian morphology. Here we use a conditional Dmrt1 transgene to show that Dmrt1 is not only necessary but also sufficient to specify male cell identity in the mouse gonad. DMRT1 expression in the ovary silenced the female sex-maintenance gene Foxl2 and reprogrammed juvenile and adult granulosa cells into Sertoli-like cells, triggering formation of structures resembling male seminiferous tubules. DMRT1 can silence Foxl2 even in the absence of the testis-determining genes Sox8 and Sox9. mRNA profiling found that DMRT1 activates many testicular genes and downregulates ovarian genes and single cell RNA-seq in transdifferentiating cells identified dynamically expressed candidate mediators of this process. Strongly upregulated genes were highly enriched on chromosome X, consistent with sexually antagonistic functions. This study provides an in vivo example of single gene reprogramming of cell sexual identity. Our findings suggest a reconsideration of mechanisms involved in human disorders of sexual development (DSD) and empirically support evolutionary models where loss or gain of Dmrt1 function promotes establishment of new vertebrate sex determination systems.
2015-02-27 | GSE64960 | GEO
Project description:Dmrt1 (doublesex and mab-3 related transcription factor 1) is a conserved transcriptional regulator of male differentiation required for testicular development in vertebrates. In mice of the 129Sv strain, loss of Dmrt1 causes a high incidence of teratomas. Mutant 129Sv germ cells undergo apparently normal differentiation up to embryonic day 13.5 (E13.5), but some cells fail to arrest mitosis and ectopically express pluripotency markers. Expression analysis and chromatin immunoprecipitation identified DMRT1 target genes whose misexpression may underly teratoma formation. Comparison of E13.5 testes gene expression between Dmrt1(+/-) and Dmrt1(-,-) animals that show high incidence of teratoma formation.
2010-07-30 | E-GEOD-18396 | biostudies-arrayexpress
Project description:Nascent human primordial germ cell-like cells (PGCLCs) can be specified with BMP2 or BMP4 together with SCF and EGF from germline competent embryonic stem cells which are maintained in the presence of inhibitors for GSK3, MEK, p38 and JNK together with FGF2, TGFβ and LIF (4i ESC). Here we discovered that Activin A and retinoic acid treatment after PGC specification induced genes expressed in migrating and gonadal PGCs in vivo, including DMRT1 and CDH5. Ectopic expression of DMRT1 and SOX17 resulted in repression of pluripotent genes as well as induction of DAZL and a subset of mitotic arrest PGC genes. Our findings provide novel insights on the roles of DMRT1 for the transition from nascent PGCs towards germline determination and molecular mechanisms of early human germline development.
2023-07-18 | GSE223035 | GEO
Project description:Nascent human primordial germ cell-like cells (PGCLCs) can be specified with BMP2 or BMP4 together with SCF and EGF from germline competent embryonic stem cells which are maintained in the presence of inhibitors for GSK3, MEK, p38 and JNK together with FGF2, TGFβ and LIF (4i ESC). Here we discovered that Activin A and retinoic acid treatment after PGC specification induced genes expressed in migrating and gonadal PGCs in vivo, including DMRT1 and CDH5. Ectopic expression of DMRT1 and SOX17 resulted in repression of pluripotent genes as well as induction of DAZL and a subset of mitotic arrest PGC genes. Our findings provide novel insights on the roles of DMRT1 for the transition from nascent PGCs towards germline determination and molecular mechanisms of early human germline development.
2023-07-18 | GSE223034 | GEO
Project description:Nascent human primordial germ cell-like cells (PGCLCs) can be specified with BMP2 or BMP4 together with SCF and EGF from germline competent embryonic stem cells which are maintained in the presence of inhibitors for GSK3, MEK, p38 and JNK together with FGF2, TGFβ and LIF (4i ESC). Here we discovered that Activin A and retinoic acid treatment after PGC specification induced genes expressed in migrating and gonadal PGCs in vivo, including DMRT1 and CDH5. Ectopic expression of DMRT1 and SOX17 resulted in repression of pluripotent genes as well as induction of DAZL and a subset of mitotic arrest PGC genes. Our findings provide novel insights on the roles of DMRT1 for the transition from nascent PGCs towards germline determination and molecular mechanisms of early human germline development.
2023-07-18 | GSE223033 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE22500: Conditional Dmrt1 knockout gene expression (phase 6) GSE22507: Conditional Dmrt1 knockout gene expression (phase 7) GSE22508: Conditional Dmrt1 knockout gene expression (phase 8) Refer to individual Series
2010-06-30 | E-GEOD-22510 | biostudies-arrayexpress
Project description:To explore the potential function of Dmrt1 in spermatogenesis, we constructed a Dmrt1-deficiency mouse model by knockdown Dmrt1 in testicular seminiferous tubule specifically
2023-09-01 | GSE212664 | GEO