DNA methylation disruption reshapes the hematopoietic differentiation landscape Journal Article

   

Authors:	Izzo, F.; Lee, S. C.; Poran, A.; Chaligne, R.; Gaiti, F.; Gross, B.; Murali, R. R.; Deochand, S. D.; Ang, C.; Wyndham Jones, P.; Nam, A. S.; Kim, K. T.; Kothen-Hill, S.; Schulman, R. C.; Ki, M.; Lhoumaud, P.; Skok, J. A.; Viny, A. D.; Levine, R. L.; Kenigsberg, E.; Abdel-Wahab, O.; Landau, D. A.
Article Title:	DNA methylation disruption reshapes the hematopoietic differentiation landscape
Abstract:	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. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords:	controlled study; human tissue; aged; unclassified drug; gene mutation; nonhuman; animal cell; mouse; erythroid precursor cell; genotype; genome-wide association study; transcription factor; cell differentiation; transcriptomics; dna methylation; genetic transduction; stem cell; cpg island; gene disruption; erythroid cell; gene loss; hematopoiesis; hematopoietic stem cell; mutation rate; transcriptome; dna binding motif; enhancer region; dna methyltransferase 3a; single cell analysis; human; male; female; priority journal; article; tet2 protein; single cell rna seq; myelomonocytic progenitor cell
Journal Title:	Nature Genetics
Volume:	52
Issue:	4
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Date Published:	2020-04-01
Start Page:	378
End Page:	387
Language:	English
DOI:	10.1038/s41588-020-0595-4
PUBMED:	32203468
PROVIDER:	scopus
PMCID:	PMC7216752
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85083041344&doi=10.1038%2fs41588-020-0595-4&partnerID=40&md5=c22e489e9d6a870c015893b2a030a250
Notes:	Article -- Export Date: 1 May 2020 -- Source: Scopus

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