Genome-wide Maps of Chromatin State in Control and DEK-deficient Hematopoietic Stem Cells [CUT&Tag]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE166433 | GEO | 2021/02/22
REPOSITORIES: GEO
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Project description:Purpose:To identify genes involved in the DEK regulating chromatin accessibility of hematopoietic stem cells (HSC) in mice, we performed ATAC-Sequence of HSC freshly sorted from mice.
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Project description:Replication stress drives functional decline in HSCs and is a major driver of BM failure in Fanconi anemia (FA). At present, how HSCs respond and counteract replication stress remains largely unknown. Using integrated multi-omics, we demonstrate that global chromatin relaxation is a prerequisite for the activation of stress-responsive genes and replication fork stabilization/progression in HSCs under replication stress. The reduced DEK (a chromatin architectural protein) contributes to the chromatin relaxation in HSCs, whereas DEK-overexpressed HSCs are confronted with a strong replication challenge, resulting in impaired HSC maintenance and hematopoiesis. Fancd2 deletion induces DEK expression and causes replication stress in HSCs, while haploinsufficiency of DEK promotes chromatin opening in Fancd2-deficient HSCs and substantially recovers HSC function. Notably, DEK expression is abnormally up-regulated in bone marrow (BM) CD34+ cells from FA patients. Inhibition of DEK significantly restores the proliferation capacity in vitro and engraftment in vivo of BM CD34+ cells from FA patients. At the molecular level, we identify that the transcriptional factor ATF2 directly promotes DEK transcription, mainly relying on the phosphorylated ATF2 (Thr69/71). Wild-type HSCs reduces DEK expression to counteract replication stress through the ATR kinase to phosphorylate ATF2 at Ser490/498. However, Fancd2 deficiency induces hyper-phosphorylation of p38 that further phosphorylates ATF2 at Thr69/71, causing DEK accumulation in HSCs. Collectively, our findings provide the first evidence of a functional link between chromatin relaxation and replication stress tolerance in HSCs, and highlight DEK as a potential molecular target for FA.
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Project description:Replication stress drives functional decline in HSCs and is a major driver of BM failure in Fanconi anemia (FA). At present, how HSCs respond and counteract replication stress remains largely unknown. Using integrated multi-omics, we demonstrate that global chromatin relaxation is a prerequisite for the activation of stress-responsive genes and replication fork stabilization/progression in HSCs under replication stress. The reduced DEK (a chromatin architectural protein) contributes to the chromatin relaxation in HSCs, whereas DEK-overexpressed HSCs are confronted with a strong replication challenge, resulting in impaired HSC maintenance and hematopoiesis. Fancd2 deletion induces DEK expression and causes replication stress in HSCs, while haploinsufficiency of DEK promotes chromatin opening in Fancd2-deficient HSCs and substantially recovers HSC function. Notably, DEK expression is abnormally up-regulated in bone marrow (BM) CD34+ cells from FA patients. Inhibition of DEK significantly restores the proliferation capacity in vitro and engraftment in vivo of BM CD34+ cells from FA patients. At the molecular level, we identify that the transcriptional factor ATF2 directly promotes DEK transcription, mainly relying on the phosphorylated ATF2 (Thr69/71). Wild-type HSCs reduces DEK expression to counteract replication stress through the ATR kinase to phosphorylate ATF2 at Ser490/498. However, Fancd2 deficiency induces hyper-phosphorylation of p38 that further phosphorylates ATF2 at Thr69/71, causing DEK accumulation in HSCs. Collectively, our findings provide the first evidence of a functional link between chromatin relaxation and replication stress tolerance in HSCs, and highlight DEK as a potential molecular target for FA.
2025-01-03 | GSE267483 | GEO
Project description:Replication stress drives functional decline in HSCs and is a major driver of BM failure in Fanconi anemia (FA). At present, how HSCs respond and counteract replication stress remains largely unknown. Using integrated multi-omics, we demonstrate that global chromatin relaxation is a prerequisite for the activation of stress-responsive genes and replication fork stabilization/progression in HSCs under replication stress. The reduced DEK (a chromatin architectural protein) contributes to the chromatin relaxation in HSCs, whereas DEK-overexpressed HSCs are confronted with a strong replication challenge, resulting in impaired HSC maintenance and hematopoiesis. Fancd2 deletion induces DEK expression and causes replication stress in HSCs, while haploinsufficiency of DEK promotes chromatin opening in Fancd2-deficient HSCs and substantially recovers HSC function. Notably, DEK expression is abnormally up-regulated in bone marrow (BM) CD34+ cells from FA patients. Inhibition of DEK significantly restores the proliferation capacity in vitro and engraftment in vivo of BM CD34+ cells from FA patients. At the molecular level, we identify that the transcriptional factor ATF2 directly promotes DEK transcription, mainly relying on the phosphorylated ATF2 (Thr69/71). Wild-type HSCs reduces DEK expression to counteract replication stress through the ATR kinase to phosphorylate ATF2 at Ser490/498. However, Fancd2 deficiency induces hyper-phosphorylation of p38 that further phosphorylates ATF2 at Thr69/71, causing DEK accumulation in HSCs. Collectively, our findings provide the first evidence of a functional link between chromatin relaxation and replication stress tolerance in HSCs, and highlight DEK as a potential molecular target for FA.
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Project description:Replication stress drives functional decline in HSCs and is a major driver of BM failure in Fanconi anemia (FA). At present, how HSCs respond and counteract replication stress remains largely unknown. Using integrated multi-omics, we demonstrate that global chromatin relaxation is a prerequisite for the activation of stress-responsive genes and replication fork stabilization/progression in HSCs under replication stress. The reduced DEK (a chromatin architectural protein) contributes to the chromatin relaxation in HSCs, whereas DEK-overexpressed HSCs are confronted with a strong replication challenge, resulting in impaired HSC maintenance and hematopoiesis. Fancd2 deletion induces DEK expression and causes replication stress in HSCs, while haploinsufficiency of DEK promotes chromatin opening in Fancd2-deficient HSCs and substantially recovers HSC function. Notably, DEK expression is abnormally up-regulated in bone marrow (BM) CD34+ cells from FA patients. Inhibition of DEK significantly restores the proliferation capacity in vitro and engraftment in vivo of BM CD34+ cells from FA patients. At the molecular level, we identify that the transcriptional factor ATF2 directly promotes DEK transcription, mainly relying on the phosphorylated ATF2 (Thr69/71). Wild-type HSCs reduces DEK expression to counteract replication stress through the ATR kinase to phosphorylate ATF2 at Ser490/498. However, Fancd2 deficiency induces hyper-phosphorylation of p38 that further phosphorylates ATF2 at Thr69/71, causing DEK accumulation in HSCs. Collectively, our findings provide the first evidence of a functional link between chromatin relaxation and replication stress tolerance in HSCs, and highlight DEK as a potential molecular target for FA.
2025-01-03 | GSE267489 | GEO
Project description:Replication stress drives functional decline in HSCs and is a major driver of BM failure in Fanconi anemia (FA). At present, how HSCs respond and counteract replication stress remains largely unknown. Using integrated multi-omics, we demonstrate that global chromatin relaxation is a prerequisite for the activation of stress-responsive genes and replication fork stabilization/progression in HSCs under replication stress. The reduced DEK (a chromatin architectural protein) contributes to the chromatin relaxation in HSCs, whereas DEK-overexpressed HSCs are confronted with a strong replication challenge, resulting in impaired HSC maintenance and hematopoiesis. Fancd2 deletion induces DEK expression and causes replication stress in HSCs, while haploinsufficiency of DEK promotes chromatin opening in Fancd2-deficient HSCs and substantially recovers HSC function. Notably, DEK expression is abnormally up-regulated in bone marrow (BM) CD34+ cells from FA patients. Inhibition of DEK significantly restores the proliferation capacity in vitro and engraftment in vivo of BM CD34+ cells from FA patients. At the molecular level, we identify that the transcriptional factor ATF2 directly promotes DEK transcription, mainly relying on the phosphorylated ATF2 (Thr69/71). Wild-type HSCs reduces DEK expression to counteract replication stress through the ATR kinase to phosphorylate ATF2 at Ser490/498. However, Fancd2 deficiency induces hyper-phosphorylation of p38 that further phosphorylates ATF2 at Thr69/71, causing DEK accumulation in HSCs. Collectively, our findings provide the first evidence of a functional link between chromatin relaxation and replication stress tolerance in HSCs, and highlight DEK as a potential molecular target for FA.
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Project description:Purpose:To identify genes and the molecular pathways involved in the DEK regulating hematopoietic stem cells (HSC) in mice, we performed RNA-Sequence of HSC freshly sorted from mice. Methods: mRNA profiles of HSC in Dekfl/fl (floxp) and Dekfl/fl,Tie2-Cre (cKO) were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000. Results:Using an optimized data analysis workflow, we mapped about 50 million sequence reads per sample to the mouse genome (build mm10) and identified 33299 transcripts in HSC (the floxp and cKO group) with BWA workflow. Conclusions: Our results represent the first detailed analysis of HSC transcriptomes in Dek-knockout mice and found that DEK regulated multiple mRNA pathways in HSC.
2021-02-22 | GSE166431 | GEO
Project description:The nuclear factor Dek is notably enriched within chromatin; nevertheless, the precise binding mechanism of Dek to the nucleosome remains elusive. In this study, we employ cryo-electron microscopy (cryo-EM) to elucidate the high-resolution structure of the Dek-Nucleosome Core Particle (NCP) complex. We identify specific domains responsible for DEK interaction with the histone octamer and DNA within the nucleosome. The veracity of these binding domains is confirmed through a series of meticulous biochemical experiments. Subsequently, cellular experiments reveal that Dek lacking nucleosome-binding capacity exhibits a deficiency in chromatin interaction. Remarkably, this impairment induces a shift towards the primitive endoderm fate in mouse embryonic stem cells, underscoring the pivotal role of Dek in determining cell fate through its nucleosomal interactions.
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Project description:The nuclear factor Dek is notably enriched within chromatin; nevertheless, the precise binding mechanism of Dek to the nucleosome remains elusive. In this study, we employ cryo-electron microscopy (cryo-EM) to elucidate the high-resolution structure of the Dek-Nucleosome Core Particle (NCP) complex. We identify specific domains responsible for DEK interaction with the histone octamer and DNA within the nucleosome. The veracity of these binding domains is confirmed through a series of meticulous biochemical experiments. Subsequently, cellular experiments reveal that Dek lacking nucleosome-binding capacity exhibits a deficiency in chromatin interaction. Remarkably, this impairment induces a shift towards the primitive endoderm fate in mouse embryonic stem cells, underscoring the pivotal role of Dek in determining cell fate through its nucleosomal interactions.
2025-01-01 | GSE281372 | GEO
Project description:Genome-wide Maps of Chromatin State in Control and DEK-deficient Hematopoietic Stem Cells [CUT&Tag]
| PRJNA700961 | ENA