Title | DNA methylation disruption reshapes the hematopoietic differentiation landscape. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Izzo F, Lee SC, Poran A, Chaligne R, Gaiti F, Gross B, Murali RR, Deochand SD, Ang C, Jones PWyndham, Nam AS, Kim K-T, Kothen-Hill S, Schulman RC, Ki M, Lhoumaud P, Skok JA, Viny AD, Levine RL, Kenigsberg E, Abdel-Wahab O, Landau DA |
Journal | Nat Genet |
Volume | 52 |
Issue | 4 |
Pagination | 378-387 |
Date Published | 2020 04 |
ISSN | 1546-1718 |
Keywords | Animals, Cell Differentiation, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, DNA-Binding Proteins, Hematopoiesis, Hematopoietic Stem Cells, Humans, Male, Mice, Mice, Transgenic, Mutation, Transcription, Genetic, Transcriptome |
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. |
DOI | 10.1038/s41588-020-0595-4 |
Alternate Journal | Nat Genet |
PubMed ID | 32203468 |
PubMed Central ID | PMC7216752 |
Grant List | R00 CA218896 / CA / NCI NIH HHS / United States R01 HL128239 / HL / NHLBI NIH HHS / United States K08 CA215317 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States R35 GM122515 / GM / NIGMS NIH HHS / United States R01 HL145283 / HL / NHLBI NIH HHS / United States DP2 CA239065 / CA / NCI NIH HHS / United States |
Related Lab:
Related Faculty:
Anna (Seung Ha) Nam, M.D.