Chromatin regulatory dynamics of early development and regional specification in a directed differentiation model of the human small intestine
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE142316 | GEO | 2021/01/27
REPOSITORIES: GEO
Similar Datasets
Project description:Chromatin regulatory dynamics of early development and regional specification in a directed differentiation model of the human small intestine
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Project description:The PIWI-interacting RNA (piRNA) pathway guides the DNA methylation of young active transposons during male mouse germline development. piRNAs tether the PIWI protein MIWI2 (PIWIL4) to the nascent transposon transcript that results in DNA methylation through SPOCD1. Transposon methylation requires exacting precision: all copies need to be methylated yet, at the same time, off-target methylation must be avoided. However, the underlying mechanisms that ensure this precision remain unknown. Here, we show that SPOCD1 directly interacts with SPIN1 (SPINDLIN1), a chromatin reader that primarily binds H3K4me3 K9me3. The prevailing assumption is that all molecular events required for piRNA-directed DNA methylation occur after the engagement of MIWI2. Interestingly, we find that SPIN1 expression precedes that of both SPOCD1 and MIWI2. Furthermore, we demonstrate that young LINE1s, but not old copies are marked by H3K4me3, H3K9me3 and SPIN1 prior to the initiation of piRNA-directed DNA methylation. We generated a Spocd1 separation-of-function allele in the mouse that encodes a SPOCD1 variant that no longer interacts with SPIN1. We found that the SPOCD1-SPIN1 interaction is essential for spermatogenesis and piRNA-directed DNA methylation of young LINE1 elements. We propose that young LINE1 elements require a two-factor authentication process for DNA methylation, the first being the recruitment of SPIN1-SPOCD1 to licence the locus and the second is MIWI2 engagement with the nascent transcript, which is also the trigger for methylation. In summary, independent events that licence, and trigger methylation underpin the basis of precision.
2024-07-23 | GSE269344 | GEO
Project description:Human pluripotent stem cells (hPSCs) are potential sources of cells for modeling disease and development, drug discovery, and regenerative medicine. However, it is important to identify factors that may impact the utility of hPSCs for these applications. In an unbiased analysis of 205 hPSC and 130 somatic samples, we identified hPSC-specific epigenetic and transcriptional aberrations in genes subject to X chromosome inactivation (XCI) and genomic imprinting, which were not corrected during directed differentiation. We also found that specific tissue types were distinguished by unique patterns of DNA hypomethylation, which were recapitulated by DNA demethylation during in vitro directed differentiation. Our results suggest that verification of baseline epigenetic status is critical for hPSC-based disease models in which the observed phenotype depends on proper XCI or imprinting, and that tissue-specific DNA methylation patterns can be accurately modeled during directed differentiation of hPSCs, even in the presence of variations in XCI or imprinting. To obtain a comprehensive view of hPSC-specific epigenomic patterns, we collected 136 hESC and 69 hiPSC samples representing more than 100 cell lines for analysis. In order to establish expected variation in human tissues, we collected 80 high-quality and well-replicated samples representing 17 distinct tissue types from multiple individuals. Finally, we selected 50 additional samples from primary cell lines of diverse origin to control for any aberrations that may arise as a general, non-hPSC-specific, consequence of in vitro manipulation. With these samples, we performed genome-wide DNA methylation and mRNA expression profiling using the Illumina Infinium 27K and 450K DNA Methylation BeadChips as well as the Illumina HT12v3 Gene Expression BeadArray.
2012-05-13 | E-GEOD-31848 | biostudies-arrayexpress
Project description:Human pluripotent stem cells (hPSCs) are potential sources of cells for modeling disease and development, drug discovery, and regenerative medicine. However, it is important to identify factors that may impact the utility of hPSCs for these applications. In an unbiased analysis of 205 hPSC and 130 somatic samples, we identified hPSC-specific epigenetic and transcriptional aberrations in genes subject to X chromosome inactivation (XCI) and genomic imprinting, which were not corrected during directed differentiation. We also found that specific tissue types were distinguished by unique patterns of DNA hypomethylation, which were recapitulated by DNA demethylation during in vitro directed differentiation. Our results suggest that verification of baseline epigenetic status is critical for hPSC-based disease models in which the observed phenotype depends on proper XCI or imprinting, and that tissue-specific DNA methylation patterns can be accurately modeled during directed differentiation of hPSCs, even in the presence of variations in XCI or imprinting. To obtain a comprehensive view of hPSC-specific epigenomic patterns, we collected 136 hESC and 69 hiPSC samples representing more than 100 cell lines for analysis. In order to establish expected variation in human tissues, we collected 80 high-quality and well-replicated samples representing 17 distinct tissue types from multiple individuals. Finally, we selected 50 additional samples from primary cell lines of diverse origin to control for any aberrations that may arise as a general, non-hPSC-specific, consequence of in vitro manipulation. With these samples, we performed genome-wide DNA methylation and mRNA expression profiling using the Illumina Infinium 27K and 450K DNA Methylation BeadChips as well as the Illumina HT12v3 Gene Expression BeadArray.
2012-05-13 | E-GEOD-30652 | biostudies-arrayexpress
Project description:Human pluripotent stem cells (hPSCs) are potential sources of cells for modeling disease and development, drug discovery, and regenerative medicine. However, it is important to identify factors that may impact the utility of hPSCs for these applications. In an unbiased analysis of 205 hPSC and 130 somatic samples, we identified hPSC-specific epigenetic and transcriptional aberrations in genes subject to X chromosome inactivation (XCI) and genomic imprinting, which were not corrected during directed differentiation. We also found that specific tissue types were distinguished by unique patterns of DNA hypomethylation, which were recapitulated by DNA demethylation during in vitro directed differentiation. Our results suggest that verification of baseline epigenetic status is critical for hPSC-based disease models in which the observed phenotype depends on proper XCI or imprinting, and that tissue-specific DNA methylation patterns can be accurately modeled during directed differentiation of hPSCs, even in the presence of variations in XCI or imprinting. To obtain a comprehensive view of hPSC-specific epigenomic patterns, we collected 136 hESC and 69 hiPSC samples representing more than 100 cell lines for analysis. In order to establish expected variation in human tissues, we collected 80 high-quality and well-replicated samples representing 17 distinct tissue types from multiple individuals. Finally, we selected 50 additional samples from primary cell lines of diverse origin to control for any aberrations that may arise as a general, non-hPSC-specific, consequence of in vitro manipulation. With these samples, we performed genome-wide DNA methylation and mRNA expression profiling using the Illumina Infinium 27K and 450K DNA Methylation BeadChips as well as the Illumina HT12v3 Gene Expression BeadArray.
2012-05-13 | E-GEOD-30653 | biostudies-arrayexpress
Project description:The PIWI-interacting RNA (piRNA) pathway guides the DNA methylation of young active transposons during male mouse germline development. piRNAs tether the PIWI protein MIWI2 (PIWIL4) to the nascent transposon transcript that results in DNA methylation through SPOCD1. Transposon methylation requires exacting precision: all copies need to be methylated yet, at the same time, off-target methylation must be avoided. However, the underlying mechanisms that ensure this precision remain unknown. Here, we show that SPOCD1 directly interacts with SPIN1, a chromatin reader that primarily binds H3K4me3 and this association is augmented by H3K9me3. The prevailing assumption is that all molecular events required for piRNA-directed DNA methylation occur after the engagement of MIWI2. Interestingly, we find that SPIN1 expression precedes that of both SPOCD1 and MIWI2. Furthermore, we demonstrate that young LINE1s, but not old copies are marked by H3K4me3 and H3K9me3 prior to the initiation of piRNA-directed DNA methylation. We generated a Spocd1 separation-of-function allele in the mouse that encodes a SPOCD1 variant that no longer interacts with SPIN1. We found that the SPOCD1-SPIN1 interaction is essential for spermatogenesis and piRNA-directed DNA methylation of young LINE1 elements. We propose that young LINE1 elements require a two-factor authentication process for DNA methylation, the first being the recruitment of SPIN1-SPOCD1 to licence the locus and the second is MIWI2 engagement with the nascent transcript, which is the trigger for methylation. In summary, independent events that licence, and trigger methylation underpin the basis of precision.
2024-09-04 | PXD041214 | Pride
Project description:Sphingolipids, ceramides and cholesterol are integral components of cellular membranes, and they also play important roles in signal transduction by regulating the dynamics of membrane receptors through their effects on membrane fluidity. Here, we combined biochemical and functional assays with single-molecule dynamic approaches to demonstrate that the local lipid environment regulates CXCR4 organization and function and modulates chemokine-triggered directed cell migration. Prolonged treatment of T cells with neutral sphingomyelinase promoted the complete and sustained breakdown of sphingomyelins and the accumulation of the corresponding ceramides, which altered both membrane fluidity and CXCR4 nanoclustering and dynamics. Under these conditions CXCR4 retained some CXCL12-mediated signaling activity but failed to promote efficient directed cell migration. Our data underscore a critical role for the local lipid composition at the cell membrane in regulating the lateral mobility of chemokine receptors, and their ability to dynamically increase receptor density at the leading edge to promote efficient cell migration
2022-04-22 | ST002150 | MetabolomicsWorkbench
Project description:In mammals, the acquisition of the germline from the soma provides the germline with an essential challenge, the necessity to erase and reset genomic methylation. In the male germline RNA-directed DNA methylation silences young active transposable elements (TEs). The PIWI protein MIWI2 (PIWIL4) and its associated PIWI-interacting RNAs (piRNAs) are proposed to tether MIWI2 to nascent TE transcripts and instruct DNA methylation. The mechanism by which MIWI2 directs de novo TE methylation is poorly understood but central to the immortality of the germline. Here, we define the interactome of MIWI2 in foetal gonocytes that are undergoing de novo genome methylation and identify a novel MIWI2-associated factor, SPOCD1, that is essential for young TE methylation and silencing. The loss of Spocd1 in mice results in male specific infertility and does not impact on piRNA biogenesis nor localization of MIWI2 to the nucleus. SPOCD1 is a nuclear protein and its expression is restricted to the period of de novo genome methylation. We found SPOCD1 co-purified in vivo with DNMT3L and DNMT3A, components of the de novo methylation machinery as well as constituents of the NURD and BAF chromatin remodelling complexes. We propose a model whereby tethering of MIWI2 to a nascent TE transcript recruits repressive chromatin remodelling activities and the de novo methylation apparatus through its association with SPOCD1. In summary, we have identified a novel and essential executor of mammalian piRNA-directed DNA methylation.
2020-06-01 | E-MTAB-7997 | biostudies-arrayexpress
Project description:The PIWI-interacting RNA (piRNA) pathway guides the DNA methylation of young active transposons during male mouse germline development. piRNAs tether the PIWI protein MIWI2 (PIWIL4) to the nascent transposon transcript that results in DNA methylation through SPOCD1. Transposon methylation requires exacting precision: all copies need to be methylated yet, at the same time, off-target methylation must be avoided. However, the underlying mechanisms that ensure this precision remain unknown. Here, we show that SPOCD1 directly interacts with SPIN1, a chromatin reader that primarily binds H3K4me3 and this association is augmented by H3K9me3. The prevailing assumption is that all molecular events required for piRNA-directed DNA methylation occur after the engagement of MIWI2. Interestingly, we find that SPIN1 expression precedes that of both SPOCD1 and MIWI2. Furthermore, we demonstrate that young LINE1s, but not old copies are marked by H3K4me3 and H3K9me3 prior to the initiation of piRNA-directed DNA methylation. We generated a Spocd1 separation-of-function allele in the mouse that encodes a SPOCD1 variant that no longer interacts with SPIN1. We found that the SPOCD1-SPIN1 interaction is essential for spermatogenesis and piRNA-directed DNA methylation of young LINE1 elements. We propose that young LINE1 elements require a two-factor authentication process for DNA methylation, the first being the recruitment of SPIN1-SPOCD1 to licence the locus and the second is MIWI2 engagement with the nascent transcript, which is the trigger for methylation. In summary, independent events that licence, and trigger methylation underpin the basis of precision.
2024-07-26 | GSE228294 | GEO
Project description:Trithorax Cxxc1-directed epigenetic dynamics licensing CD4+ T cell differentiation
| PRJNA669675 | ENA