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CRISPR/dCas9 DNA methylation editing is heritable during human haematopoiesis and can impair differentiation in vivo [methylation array]

ABSTRACT: CRISPR/dCas9 DNA methylation editing is heritable during human haematopoiesis and can impair differentiation in vivo [methylation array]

PROVIDER: PRJNA918412 | ENA |

REPOSITORIES: ENA

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CRISPR/dCas9 DNA methylation editing is heritable during human haematopoiesis and can impair differentiation in vivo.

Project description:CRISPR/dCas9 DNA methylation editing is heritable during human haematopoiesis and can impair differentiation in vivo.

| PRJNA918411 | ENA

CRISPR/dCas9 DNA methylation editing is heritable during human haematopoiesis and can impair differentiation in vivo [methylation array]

Project description:Ageing is associated with an abnormal increase of DNA methylation in human gene promoters, including in the bone marrow stem cells. DNA methylation patterns are further perturbed in haematological malignancies such as acute myeloid leukaemia (AML) but the physiological significance of such epigenetic changes is unknown. Using epigenetic editing of human stem/progenitor cells (HSPCs), we show evidence that p15 methylation affects haematopoiesis in vivo. We edited the CDKN2B (p15) promoter and ARF (p14) using dCas9-3A3L and observed DNA methylation spreading beyond the location of the gRNA. We find that despite a transient delivery system, DNA methylation is maintained during myeloid differentiation in vitro, and hypermethylation of the p15 promoter reduces gene expression. In vivo, edited human HSPCs can engraft the bone marrow of mice and targeted DNA methylation is maintained in HSPCs long term. Moreover, we identified how the epigenetic changes are conserved and inherited in both myeloid and lymphoid lineages. Although the proportion of myeloid (CD33+) and lymphoid (CD19+) cells is unaffected, monocyte (CD14+) populations decreased and granulocytes (CD66b+) increased in mice engrafted with p15 hypermethylated cells. We also observe significant changes in the proportions of multipotent and committed progenitor cells. This may have clinical relevance since we found that p15 promoter methylation is present in the peripheral blood of patients with clonal haematopoiesis. Our study shows DNA methylation can be targeted and maintained in human HSPCs and demonstrated functional relevance of aberrant DNA methylation on the p15 locus. As such, other ageing associated aberrant DNA methylation may impact haematopoiesis in vivo.

2023-08-30 | GSE222178 | GEO

CRISPR/dCas9 DNA methylation editing is heritable during human haematopoiesis and can impair differentiation in vivo [Targeted BS-seq]

Project description:CRISPR/dCas9 DNA methylation editing is heritable during human haematopoiesis and can impair differentiation in vivo [Targeted BS-seq]

| PRJNA918419 | ENA

CRISPR/dCas9 DNA methylation editing is heritable during human haematopoiesis and can impair differentiation in vivo [Targeted BS-seq]

2023-08-30 | GSE222179 | GEO

CRISPR/dCas9 DNA methylation editing is heritable during human haematopoiesis and can impair differentiation in vivo.

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-08-30 | GSE222181 | GEO

CRISPR/dCas9 DNA methylation editing is heritable during human hematopoiesis and shapes immune progeny [RNA-seq]

Project description:CRISPR/dCas9 DNA methylation editing is heritable during human hematopoiesis and shapes immune progeny [RNA-seq]

| PRJNA981091 | ENA

Inhibition of uPA expression by CRISPR-dCas9 DNA methyltransferases

Project description:We report the generation of CRISPR-dCas9 DNA methyltransferases to mediate targeted DNA methylation. Using the dCas9-BFP-DNMT3A and dCas9-BFP-DNMT3B methyltransferases, we have demonstrated that these two methyltransferase can mediate targeted methylation in three human genes tested: uPA, TGFBR3, and CDKN2A in human HEK293T cells. We also showed that these methyltransferases could mediate gene inhibition. five samples co-transfected with five uPA sgRNAs and each of the four dCas9 fusions, or control transfection with pUC19 plasmid

2016-06-01 | E-GEOD-74935 | biostudies-arrayexpress

CRISPR/dCas9 DNA methylation editing is heritable during human hematopoiesis and shapes immune progeny [RNA-seq]

Project description:Aging is associated with an abnormal increase of DNA methylation in human gene promoters, including in bone marrow stem cells. DNA methylation patterns are further perturbed in hematological malignancies such as acute myeloid leukemia (AML) but the physiological significance of such epigenetic changes is unknown. Using epigenetic editing of human stem/progenitor cells (HSPCs), we show that p15 methylation affects hematopoiesis in vivo. We edited the CDKN2B (p15) promoter and ARF (p14) using dCas9-3A3L and observed DNA methylation spreading beyond the gRNA location. We find that despite a transient delivery system, DNA methylation is maintained during myeloid differentiation in vitro, and hypermethylation of the p15 promoter reduces gene expression. In vivo, edited human HSPCs can engraft the bone marrow of mice and targeted DNA methylation is maintained in HSPCs long term. Moreover, epigenetic changes are conserved and inherited in both myeloid and lymphoid lineages. Although the proportion of myeloid (CD33+) and lymphoid (CD19+) cells is unaffected, monocyte (CD14+) populations decreased and granulocytes (CD66b+) increased in mice engrafted with p15 hypermethylated HSPCs. Monocytes derived from p15 hypermethylated HSPCs appear to be activated and show increased inflammatory transcriptional programs. We believe these findings have clinical relevance since we found p15 promoter methylation in the peripheral blood of patients with clonal hematopoiesis. Our study shows DNA methylation can be targeted and maintained in human HSPCs and demonstrated functional relevance of aberrant DNA methylation on the p15 locus. As such, other ageing associated aberrant DNA methylation may impact hematopoiesis in vivo.

2023-08-30 | GSE234342 | GEO

GATA2 mitotic bookmarking is required for definitive haematopoiesis [ChIP-seq]

Project description:In mitosis, most transcription factors detach from chromatin, but some are retained and bookmark genomic sites. Mitotic bookmarking has been implicated in lineage inheritance, pluripotency and reprogramming. However, the biological significance of this mechanism in vivo remains unclear. Here, we address mitotic retention of the hemogenic factors GATA2, GFI1B and FOS during haematopoietic specification. We show that GATA2 remains bound to chromatin throughout mitosis, in contrast to GFI1B and FOS, via C-terminal zinc finger-mediated DNA binding. GATA2 bookmarks a subset of its interphase targets that are co-enriched for RUNX1 and other regulators of definitive haematopoiesis. Remarkably, homozygous mice harbouring the cyclin B1 mitosis degradation domain upstream Gata2 partially phenocopy knockout mice. Degradation of GATA2 at mitotic exit abolishes definitive haematopoiesis at aorta-gonad-mesonephros, placenta and foetal liver, but does not impair yolk sac haematopoiesis. Our findings implicate GATA2-mediated mitotic bookmarking as critical for definitive haematopoiesis and highlight a dependency on bookmarkers for lineage commitment.

2023-06-27 | GSE207551 | GEO

Intergenerational hormesis is regulated by heritable 18S rRNA methylation 18S rRNA methylation is heritably transmitted to regulate intergenerational hormesis

Project description:Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are unknown. Here, we perform metabolic methyl-labelling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans. We find that methylation is transmitted to descendants in proteins, RNA, DNA and lipids. We further find that in response to parental starvation, naïve progeny display reduced fertility, increased heat stress resistance, and extended longevity. This intergenerational hormesis is accompanied by a heritable increase in N6’-dimethyl adenosine (m6,2A) on the 18S ribosomal RNA at adenosines 1735 and 1736. We identified DIMT-1 as the m6,2A methyltransferase in C. elegans and find that dimt-1 is required for the intergenerational hormesis phenotypes. Together this study provides the first labeling and tracking of heritable non-genetic material across generations and demonstrates the importance of rRNA methylation for regulating the heritable response to starvation

2022-05-01 | GSE175363 | GEO

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