Clonal Hematopoiesis Landscape in Frequent Blood Donors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1227157 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32458300_1.fastq.gz | Fastqsanger.gz | |||
| SRR32458300_2.fastq.gz | Fastqsanger.gz | |||
| SRR32458301_1.fastq.gz | Fastqsanger.gz | |||
| SRR32458301_2.fastq.gz | Fastqsanger.gz | |||
| SRR32458302_1.fastq.gz | Fastqsanger.gz |
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Project description:Donor blood saves lives, yet the potential impact of recurrent large-volume phlebotomy on donor health and hematopoietic stem cells (HSCs) remains largely unexplored. In our study, we conducted a comprehensive screening of 217 older male volunteer donors with a history of extensive blood donation (>100 life-time donations) to investigate the phenomenon of clonal hematopoiesis (CH). No significant difference in the overall incidence of CH was found in frequent donors (FD) compared to sporadic donors (<10 life-time donations, 212 donors). However, upon deeper analysis of mutations in DNMT3A, the most commonly affected gene in CH, we observed distinct mutational patterns between the FD and age/sex matched control donor (CD) cohorts. Functional analysis of FD enriched DNMT3A variants examined in CRISPR-edited human HSCs demonstrated their competitive outgrowth potential upon stimulation with erythropoietin (EPO), a hormone which increases in response to blood loss. In contrast, clones harboring leukemogenic DNMT3A R882 mutations increase upon stimulation with IFNy. Through concurrent mutational and immunophenotypic profiling of primary samples at single cell resolution, a myeloid bias of premalignant R882 mutant HSCs was found, while no significant lineage bias was observed in HSCs harboring EPO responsive DNMT3A variants. The latter exhibited preferential erythroid differentiation when persistent erythropoietic stress was applied to CRISPR-edited human HSC xenografts. Our data demonstrate a nuanced ongoing Darwinian evolution at the somatic stem cell level, with EPO identified as a novel environmental factor that favors HSCs carrying certain DNMT3A mutations.
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Project description:Clonal hematopoiesis of indeterminate potential (CHIP) has been found to be associated with atherosclerotic cardiovascular disease (ASCVD). S-adenosylhomocysteine (SAH) is hydrolyzed by SAH hydrolase (SAHH) to homocysteine and adenosine. High levels of SAH and homocysteine has been considered as risk factors of ASCVD. However, the effect and mechanism of SAHH deficiency on clonal hematopoiesis in atherogenesis is still unknown. Now we demonstrated that heterozygote knockout of SAHH accelerated clonal expansion of hematopoietic cells and promoted the development of atherosclerosis. Specifically, myeloid cells-deficient SAHH was sufficient to promote the clonal hematopoiesis in atherogenesis. SAHH deficiency promoted proinflammatory genes expression in LPS/IFN-γ–stimulated macrophages. Mechanistically, SAHH ablation led to SAH accumulation and inhibited DNMT3a-mediated methylation of Nfkb2 and increased its transcriptional activation. On the contrary, SAHH deficiency resulted in DNMT3c-mediated hypermethylation of PPARg and repressed its expression, which is a negative regulator of Nfkb2-IL6 pathway. Furthermore, SAHH deletion induced downregulation of adenosine-AMPK-TET2 and reduced recruitment of HDAC2 and DNMT3a to activate the expression of NFkb2. Knockdown of NFkb2 or IL6 neutralizing antibody repressed inflammation and alleviated SAHH deficiency-accelerated clonal hematopoiesis and atherosclerosis. Finally, high plasma SAH levels were positively associated with IL6 and risk of CHIP in patients with CAD. Overall, these findings reveal that SAHH deficiency accelerated clonal hematopoiesis and atherosclerosis via epigenetic regulation of inflammation.
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Project description:Clonal hematopoiesis of indeterminate potential (CHIP) has been found to be associated with atherosclerotic cardiovascular disease (ASCVD). S-adenosylhomocysteine (SAH) is hydrolyzed by SAH hydrolase (SAHH) to homocysteine and adenosine. High levels of SAH and homocysteine has been considered as risk factors of ASCVD. However, the effect and mechanism of SAHH deficiency on clonal hematopoiesis in atherogenesis is still unknown. Now we demonstrated that heterozygote knockout of SAHH accelerated clonal expansion of hematopoietic cells and promoted the development of atherosclerosis. Specifically, myeloid cells-deficient SAHH was sufficient to promote the clonal hematopoiesis in atherogenesis. SAHH deficiency promoted proinflammatory genes expression in LPS/IFN-γ–stimulated macrophages. Mechanistically, SAHH ablation led to SAH accumulation and inhibited DNMT3a-mediated methylation of Nfkb2 and increased its transcriptional activation. On the contrary, SAHH deficiency resulted in DNMT3c-mediated hypermethylation of PPARg and repressed its expression, which is a negative regulator of Nfkb2-IL6 pathway. Furthermore, SAHH deletion induced downregulation of adenosine-AMPK-TET2 and reduced recruitment of HDAC2 and DNMT3a to activate the expression of NFkb2. Knockdown of NFkb2 or IL6 neutralizing antibody repressed inflammation and alleviated SAHH deficiency-accelerated clonal hematopoiesis and atherosclerosis. Finally, high plasma SAH levels were positively associated with IL6 and risk of CHIP in patients with CAD. Overall, these findings reveal that SAHH deficiency accelerated clonal hematopoiesis and atherosclerosis via epigenetic regulation of inflammation.
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