Germline ERCC6L2 mutations lead to impaired erythropoiesis and reshaping of the bone marrow niche
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA787532 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17180500_1.fastq.gz | Fastqsanger.gz | |||
| SRR17180500_2.fastq.gz | Fastqsanger.gz | |||
| SRR17180471_1.fastq.gz | Fastqsanger.gz | |||
| SRR17180471_2.fastq.gz | Fastqsanger.gz | |||
| SRR17180472_1.fastq.gz | Fastqsanger.gz |
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Project description:Despite the inclusion of inherited myeloid malignancies as a separate entity in the WHO Classification, our understanding of the etiology of familial leukemia remains limited. ERCC6L2-deficiency is a rare, life-threatening inherited condition that gives rise to bone marrow failure (BMF), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) resulting from germline mutations in DNA repair factor ERCC6L2. Here we employ a lentiviral shRNA approach to functionally characterize the impact of ERCC6L2 loss on hematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs). By combining cell culture assays and transcriptomic analysis of knockdown and ERCC6L2-mutated patient cells, we find that ERCC6L2-deficiency reduces HSPC clonogenic potential and delays erythropoiesis, while in MSCs it induces a significant lineage skewing, with increased osteogenesis and suppressed adipogenesis. Altogether, we demonstrate that ERCC6L2-deficiency impacts both hematopoietic and stromal compartments, and that our ex vivo model recapitulates patient phenotypes, providing a robust system to study germline mutations in hematological malignancies.
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Project description:Despite the inclusion of inherited myeloid malignancies as a separate entity in the World Health Organization Classification, many established predisposing loci continue to lack functional characterization. While germline mutations in the DNA repair factor ERCC excision repair 6 like 2 (ERCC6L2) give rise to bone marrow failure and acute myeloid leukaemia, their consequences on normal haematopoiesis remain unclear. To functionally characterise the dual impact of germline ERCC6L2 loss on human primary haematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs), we challenged ERCC6L2-silenced and patient-derived cells ex vivo. Here, we show for the first time that ERCC6L2-deficiency in HSPCs significantly impedes their clonogenic potential and leads to delayed erythroid differentiation. This observation was confirmed by CIBERSORTx RNA-sequencing deconvolution performed on ERCC6L2-silenced erythroid-committed cells, which demonstrated higher proportions of polychromatic erythroblasts and reduced orthochromatic erythroblasts versus controls. In parallel, we demonstrate that the consequences of ERCC6L2-deficiency are not limited to HSPCs, as we observe a striking phenotype in patient-derived and ERCC6L2-silenced MSCs, which exhibit enhanced osteogenesis and suppressed adipogenesis. Altogether, our study introduces a valuable surrogate model to study the impact of inherited myeloid mutations and highlights the importance of accounting for the influence of germline mutations in HSPCs and their microenvironment.
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Project description:Structurally complex genomic regions, such as centromeres, are inherently difficult to duplicate. The mechanism that underlies centromere inheritance is not well understood, and one of the key questions relates to the reassembly of centromeric chromatin following DNA replication. Here we define the SNF2 ATPase ERCC6L2 as a key regulator of this process. ERCC6L2 accumulates at centromeres and promotes efficient deposition of core centromeric factors. Our genomic analyses show that ERCC6L2 deficiency erodes centromeric chromatin, leading to unrestrained replication of centromeric DNA. We also establish that, beyond centromeres, ERCC6L2 facilitates replication at genomic repeats and non-canonical DNA structures. Notably, ERCC6L2 interacts with the major DNA replication factor PCNA through an atypical peptide, presented here as a co-crystal structure. Finally, we examine ERCC6L2 activities at DNA breaks, and show that it acts to restrict end resection independently of the 53BP1-REV7-Shieldin complex. Our observations allow us to propose a mechanistic model of ERCC6L2 activity, which reconciles its seemingly distinct functions in DNA repair and DNA replication. Together, these findings provide a new molecular context for studies linking ERCC6L2 to human disease.
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Project description:ERCC6L2 is a recently characterized component in DNA damage repair. To investigate its function in chromosome translocation, we conducted a study using K562 and HEK293T cell lines. We introduced twinned DNA double-strand breaks (DSBs) or genome-wide DSBs into these cell lines via nucleofection and transfection, respectively. Subsequently, we employed high-throughput genome translocation sequencing (HTGTS) to capture the translocation events (i.e., ligation between "prey(s)" and "bait") and the rejoining events (i.e., direct repair within the "bait" locus) under different conditions, including with or without ERCC6L2 deletion. We quantified the number of translocation events by normalizing them to the number of rejoining events, denoted as TL. Interestingly, ERCC6L2 deletion led to an increase in TL, indicating a higher frequency of translocations.
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