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DNA methylation disruption reshapes the hematopoietic differentiation landscape

ABSTRACT: DNA methylation disruption reshapes the hematopoietic differentiation landscape

PROVIDER: PRJNA513958 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10480100.fastq.gz	Fastqsanger.gz
	SRR10480200.fastq.gz	Fastqsanger.gz
	SRR10480300.fastq.gz	Fastqsanger.gz
	SRR10480400.fastq.gz	Fastqsanger.gz
	SRR10480500.fastq.gz	Fastqsanger.gz

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DNA methylation disruption reshapes the hematopoietic differentiation landscape.

Project description:Mutations in genes involved in DNA methylation (DNAme; for example, TET2 and DNMT3A) are frequently observed in hematological malignancies1-3 and clonal hematopoiesis4,5. Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid versus myelomonocytic progenitors following Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells. To reconcile genome-wide DNAme changes with specific erythroid versus myelomonocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A-mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motif.

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DNA methylation disruption reshapes the hematopoietic differentiation landscape

Project description:Somatic mutations in genes implicated in DNA methylation (DNAme; e.g., TET2, DNMT3A and IDH2), are frequently observed in hematological malignancies, as well as in clonal hematopoiesis (CH). Yet, how these mutations disrupt the hematopoietic differentiation topology remains largely unknown. By applying complementary single-cell sequencing approaches to murine bone marrow hematopoietic stem and progenitor cells, we observe that mutations in DNAme modifiers result in significantly altered differentiation topology. In particular, we find shifts in the frequencies of erythroid vs. myelo-monocytic progenitors, which can be traced back to fate-priming skews in the earliest uncommitted hematopoietic stem cells (HSCs). DNAme analysis both in open chromatin regions and at single-cell resolution, demonstrate that methylation changes resulting from DNAme modifier disruption are distributed stochastically across the genome. To reconcile the distributed nature of DNAme changes with the deterministic erythroid vs. myelo-monocytic topological skews, our data implicate differential sensitivity of key transcription factors to global methylation changes due to biases in CpG enrichment in their binding motifs. Finally, by coupling single-cell whole transcriptome analysis with targeted genotyping, we observe a similar skew in early transcriptional priming impact human CH bone marrow progenitors in an individual with DNMT3A-755S mutation. Thus, our results provide evidence that DNAme encodes topological information for hematopoietic differentiation.

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