Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation

  • Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yizhak, K. et al. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 364, eaaw0726 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yokoyama, A. et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature 565, 312–317 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • Yoshida, K. et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature 578, 266–272 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Martincorena, I. et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mustjoki, S. & Young, N. S. Somatic mutations in ‘benign’ disease. N. Engl. J. Med. 384, 2039–2052 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • Shlush, L. I. et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Xie, M. et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20, 1472–1478 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Steensma, D. P. et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126, 9–16 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Young, A. L., Challen, G. A., Birmann, B. M. & Druley, T. E. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7, 12484 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zink, F. et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742–752 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Champion, K. M., Gilbert, J. G. R., Asimakopoulos, F. A., Hinshelwood, S. & Green, A. R. Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes. Br. J. Haematol. 97, 920–926 (1997).

    CAS 
    PubMed 

    Google Scholar 

  • SanMiguel, J. M. et al. Cell-extrinsic stressors from the aging bone marrow (BM) microenvironment promote Dnmt3a-mutant clonal hematopoiesis. Blood 134 (Suppl), 5 (2019).

    Google Scholar 

  • Terao, C. et al. Chromosomal alterations among age-related haematopoietic clones in Japan. Nature 584, 130–135 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Watson, C. J. et al. The evolutionary dynamics and fitness landscape of clonal hematopoiesis. Science 367, 1449–1454 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • Teixeira, V. H. et al. Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions. Nat. Med. 25, 517–525 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • Steensma, D. P. & Ebert, B. L. Clonal hematopoiesis as a model for premalignant changes during aging. Exp. Hematol. 83, 48–56 (2020).

    PubMed 

    Google Scholar 

  • Desai, P. et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat. Med. 24, 1015–1023 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Papaemmanuil, E. et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122, 3616–3627 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Abelson, S. et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 559, 400–404 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Buscarlet, M. et al. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130, 753–762 (2017).

    CAS 
    PubMed 

    Google Scholar 

  • Young, A. L., Spencer Tong, R., Birmann, B. M. & Druley, T. E. Clonal hematopoiesis and risk of acute myeloid leukemia. Haematologica 104, 2410–2417 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jeong, M. et al. Loss of Dnmt3a immortalizes hematopoietic stem cells in vivo. Cell Rep. 23, 1–10 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ostrander, E. L. et al. Divergent effects of Dnmt3a and Tet2 mutations on hematopoietic progenitor cell fitness. Stem Cell Rep. 14, 551–560 (2020).

    CAS 

    Google Scholar 

  • Koya, J. et al. DNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation. Nat. Commun. 7, 10924 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kim, S. J. et al. A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells. Blood 122, 4086–4089 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Russler-Germain, D. A. et al. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell 25, 442–454 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nam, A. S. et al. Somatic mutations and cell identity linked by genotyping of transcriptomes. Nature 571, 355–360 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gaiti, F. et al. Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia. Nature 569, 576–580 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mouhieddine, T. H. et al. Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant. Nat. Commun. 11, 2996 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Smith, T., Heger, A. & Sudbery, I. UMI-tools: modeling sequencing errors in Unique Molecular Identifiers to improve quantification accuracy. Genome Res. 27, 491–499 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tickle, T., Tirosh, I., Georgescu, C., Brown, M. & Haas, B. inferCNV of the Trinity CTAT Project (Broad Institute of MIT and Harvard, 2019).

  • Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902 e21 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pellin, D. et al. A comprehensive single cell transcriptional landscape of human hematopoietic progenitors. Nat. Commun. 10, 2395 (2019).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Challen, G. A. et al. Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells. Cell Stem Cell 15, 350–364 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2011).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Cao, J. et al. The single-cell transcriptional landscape of mammalian organogenesis. Nature 566, 496–502 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Trapnell, C. et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381–386 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Guryanova, O. A. et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat. Med. 22, 1488–1495 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Velten, L. et al. Human haematopoietic stem cell lineage commitment is a continuous process. Nat. Cell Biol. 19, 271–281 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • La Manno, G. et al. RNA velocity of single cells. Nature 560, 494–498 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Bergen, V., Lange, M., Peidli, S., Wolf, F. A. & Theis, F. J. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. 38, 1408–1414 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • Clay, D. et al. CD9 and megakaryocyte differentiation. Blood 97, 1982–1989 (2001).

    CAS 
    PubMed 

    Google Scholar 

  • Noetzli, L. J., French, S. L. & Machlus, K. R.New insights into the differentiation of megakaryocytes from hematopoietic progenitors. Arterioscler. Thromb. Vasc. Biol. 39, 1288–1300 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Slupsky, J. R. et al. The platelet antigens CD9, CD42 and integrin alphaIIbbetaIIIa can be topographically associated and transduce functionally similar signals. Eur. J. Biochem. 244, 168–175 (1997).

    CAS 
    PubMed 

    Google Scholar 

  • Dai, Y. J. et al. Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement. Proc. Natl Acad. Sci. USA 114, 5237–5242 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Thol, F. et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J. Clin. Oncol. 29, 2889–2896 (2011).

    CAS 
    PubMed 

    Google Scholar 

  • Xu, J. et al. DNMT3A Arg882 mutation drives chronic myelomonocytic leukemia through disturbing gene expression/DNA methylation in hematopoietic cells. Proc. Natl Acad. Sci. USA 111, 2620–2625 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Saito, Y. et al. Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci. Transl. Med. 2, 17ra9 (2010).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Tsuboi, N., Asano, K., Lauterbach, M. & Mayadas, T. N. Human neutrophil Fcgamma receptors initiate and play specialized nonredundant roles in antibody-mediated inflammatory diseases. Immunity 28, 833–846 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lanier, L. L., Corliss, B. C., Wu, J., Leong, C. & Phillips, J. H. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391, 703–707 (1998).

    CAS 
    PubMed 

    Google Scholar 

  • Bouchon, A., Hernández-Munain, C., Cella, M. & Colonna, M. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J. Exp. Med. 194, 1111–1122 (2001).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Karulf, M., Kelly, A., Weinberg, A. D. & Gold, J. A. OX40 ligand regulates inflammation and mortality in the innate immune response to sepsis. J. Immunol. 185, 4856–4862 (2010).

    CAS 
    PubMed 

    Google Scholar 

  • Leoni, C. et al. Dnmt3a restrains mast cell inflammatory responses. Proc. Natl Acad. Sci. USA 114, E1490–E1499 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fuster, J. J. et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jaiswal, S. & Libby, P. Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nat. Rev. Cardiol. 17, 137–144 (2019).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111–121 (2017).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Vester, S. K. et al. Nucleolin acts as the receptor for C1QTNF4 and supports C1QTNF4-mediated innate immunity modulation. J. Biol. Chem. 296, 100513 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, Q. et al. Identification of C1qTNF-related protein 4 as a potential cytokine that stimulates the STAT3 and NF-κB pathways and promotes cell survival in human cancer cells. Cancer Lett. 308, 203–214 (2011).

    CAS 
    PubMed 

    Google Scholar 

  • Ramalingam, P. et al. Chronic activation of endothelial MAPK disrupts hematopoiesis via NFKB dependent inflammatory stress reversible by SCGF. Nat. Commun. 11, 666 (2020).

  • Shen, B. et al. Integrin alpha11 is an Osteolectin receptor and is required for the maintenance of adult skeletal bone mass. eLife 8, e42274 (2019).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Ito, C. et al. Serum stem cell growth factor for monitoring hematopoietic recovery following stem cell transplantation. Bone Marrow Transpl. 32, 391–398 (2003).

    CAS 

    Google Scholar 

  • Wingender, E., Dietze, P., Karas, H. & Knüppel, R. TRANSFAC: a database on transcription factors and their DNA binding sites. Nucleic Acids Res. 24, 238–241 (1996).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ben-Porath, I. et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet. 40, 499–507 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Coller, H. A. et al. Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc. Natl Acad. Sci. USA 97, 3260–3265 (2000).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Delgado, M. D. & León, J. Myc roles in hematopoiesis and leukemia. Genes Cancer 1, 605–616 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Guo, Y. et al. c-Myc-mediated control of cell fate in megakaryocyte–erythrocyte progenitors. Blood 114, 2097–2106 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mayers, S. et al. Establishment of an erythroid progenitor cell line capable of enucleation achieved with an inducible c-Myc vector. BMC Biotech. 19, 21 (2019).

    Google Scholar 

  • Vaisvila, R. et al. Enzymatic methyl sequencing detects DNA methylation at single-base resolution from picograms of DNA. Genome Res. 31, 1280–1289 (2021).

    PubMed Central 

    Google Scholar 

  • Picelli, S. et al. Full-length RNA-seq from single cells using Smart-seq2. Nat. Protoc. 9, 171–181 (2014).

    CAS 
    PubMed 

    Google Scholar 

  • Spencer, D. H. et al. CpG island hypermethylation mediated by DNMT3A is a consequence of AML progression. Cell 168, 801–816 e13 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Glass, J. L. et al. Epigenetic identity in AML depends on disruption of nonpromoter regulatory elements and is affected by antagonistic effects of mutations in epigenetic modifiers. Cancer Discov. 7, 868–883 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Vaisvila, R. et al. Enzymatic methyl sequencing detects DNA methylation at single-base resolution from picograms of DNA. Genome Res. 31, 1280–1289 (2021).

    PubMed Central 

    Google Scholar 

  • Wang, J. et al. Double restriction-enzyme digestion improves the coverage and accuracy of genome-wide CpG methylation profiling by reduced representation bisulfite sequencing. BMC Genomics 14, 11 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Andersson, R. et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455–461 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Davis, C. A. et al. The encyclopedia of DNA elements (ENCODE): data portal update. Nucleic Acids Res. 46, D794–D801 (2018).

    CAS 
    PubMed 

    Google Scholar 

  • Adelman, E. R. et al. Aging human hematopoietic stem cells manifest profound epigenetic reprogramming of enhancers that may predispose to leukemia. Cancer Discov. 9, 1080–1101 (2019).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Jeong, M. et al. Large conserved domains of low DNA methylation maintained by Dnmt3a. Nat. Genet. 46, 17–23 (2014).

    CAS 
    PubMed 

    Google Scholar 

  • Zhang, X. et al. Large DNA methylation nadirs anchor chromatin loops maintaining hematopoietic stem cell identity. Mol. Cell 78, 506–521 e6 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hawkins, R. D. et al. Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell 6, 479–491 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Margueron, R. & Reinberg, D. The Polycomb complex PRC2 and its mark in life. Nature 469, 343–349 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mohn, F. et al. Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol. Cell 30, 755–766 (2008).

    CAS 
    PubMed 

    Google Scholar 

  • Xie, H. et al. Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific manner. Cell Stem Cell 14, 68–80 (2014).

    CAS 
    PubMed 

    Google Scholar 

  • Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

    Google Scholar 

  • Emperle, M. et al. Mutations of R882 change flanking sequence preferences of the DNA methyltransferase DNMT3A and cellular methylation patterns. Nucleic Acids Res. 47, 11355–11367 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Anteneh, H., Fang, J. & Song, J. Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation. Nat. Commun. 11, 2294 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yin, Y. et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 356, eaaj2239 (2017).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Prendergast, G. C. & Ziff, E. B. Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. Science 251, 186–189 (1991).

    CAS 
    PubMed 

    Google Scholar 

  • Tate, P. H. & Bird, A. P. Effects of DNA methylation on DNA-binding proteins and gene expression. Curr. Opin. Genet Dev. 3, 226–231 (1993).

    CAS 
    PubMed 

    Google Scholar 

  • Grau, J., Schmidt, F. & Schulz, M.H. Widespread effects of DNA methylation and intra-motif dependencies revealed by novel transcription factor binding models. Preprint at bioRxiv https://doi.org/10.1101/2020.10.21.348193 (2020).

  • Takubo, K. et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7, 391–402 (2010).

    CAS 
    PubMed 

    Google Scholar 

  • Krock, B. L. et al. The aryl hydrocarbon receptor nuclear translocator is an essential regulator of murine hematopoietic stem cell viability. Blood 125, 3263–3272 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mariani, C. J. et al. TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma. Cell Rep. 7, 1343–1352 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, Y. et al. Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation. Nucleic Acids Res. 44, 7173–7188 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Huang, S., Li, X., Yusufzai, T. M., Qiu, Y. & Felsenfeld, G. USF1 recruits histone modification complexes and is critical for maintenance of a chromatin barrier. Mol. Cell. Biol. 27, 7991–8002 (2007).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Arnaud, L. et al. A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia. Am. J. Hum. Genet. 87, 721–727 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Grosselin, K. et al. High-throughput single-cell ChIP-seq identifies heterogeneity of chromatin states in breast cancer. Nat. Genet. 51, 1060–1066 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • Rotem, A. et al. Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state. Nat. Biotechnol. 33, 1165–1172 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang, Q. et al. CoBATCH for high-throughput single-cell epigenomic profiling. Mol. Cell 76, 206–216 e7 (2019).

    CAS 
    PubMed 

    Google Scholar 

  • Fu, L. et al. Predicting transcription factor binding in single cells through deep learning. Sci. Adv. 6, eaba9031 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • Ugarte, F. et al. Progressive chromatin condensation and H3K9 methylation regulate the differentiation of embryonic and hematopoietic stem cells. Stem Cell Rep. 5, 728–740 (2015).

    CAS 

    Google Scholar 

  • Martin, E. W. et al. Chromatin accessibility maps provide evidence of multilineage gene priming in hematopoietic stem cells. Epigenetics Chromatin 14, 2 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Granja, J. M. et al. Single-cell multiomic analysis identifies regulatory programs in mixed-phenotype acute leukemia. Nat. Biotechnol. 37, 1458–1465 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Setty, M. et al. Characterization of cell fate probabilities in single-cell data with Palantir. Nat. Biotechnol. 37, 451–460 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Stoeckius, M. et al. Simultaneous epitope and transcriptome measurement in single cells. Nat. Methods 14, 865–868 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zavidij, O. et al. Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma. Nat. Cancer 1, 493–506 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Izzo, F. et al. DNA methylation disruption reshapes the hematopoietic differentiation landscape. Nat. Genet. 52, 378–387 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003).

    CAS 
    PubMed 

    Google Scholar 

  • Liu, Y. et al. Convergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation. Nat. Commun. 12, 6323 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lu, R. et al. A model system for studying the DNMT3A hotspot mutation (DNMT3A(R882)) demonstrates a causal relationship between its dominant-negative effect and leukemogenesis. Cancer Res. 79, 3583–3594 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • van Galen, P. et al. The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress. Nature 510, 268–272 (2014).

    PubMed 

    Google Scholar 

  • Rodriguez-Meira, A. et al. Unravelling intratumoral heterogeneity through high-sensitivity single-cell mutational analysis and parallel RNA sequencing. Mol. Cell 73, 1292–1305 e8 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Petti, A. A. et al. A general approach for detecting expressed mutations in AML cells using single cell RNA-sequencing. Nat. Commun. 10, 3660 (2019).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Ludwig, L. S. et al. Lineage tracing in humans enabled by mitochondrial mutations and single-cell genomics. Cell 176, 1325–1339 e22 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nam, A. S., Chaligne, R. & Landau, D. A. Integrating genetic and non-genetic determinants of cancer evolution by single-cell multi-omics. Nat. Rev. Genet. 22, 3–18 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • ENCODE Project Consortium.An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

    Google Scholar 

  • Saxonov, S., Berg, P. & Brutlag, D. L. A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc. Natl Acad. Sci. USA 103, 1412–1417 (2006).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Aibar, S. et al. SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083–1086 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gothert, J. R. et al. In vivo fate-tracing studies using the Scl stem cell enhancer: embryonic hematopoietic stem cells significantly contribute to adult hematopoiesis. Blood 105, 2724–2732 (2005).

    PubMed 

    Google Scholar 

  • Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tange, O. GNU Parallel 20200622. Computer Program. Zenodo https://doi.org/10.5281/zenodo.3956817 (2020).

  • Yu, G., Wang, L.-G., Han, Y. & He, Q.-Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284–287 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Granja, J. M. et al. ArchR is a scalable software package for integrative single-cell chromatin accessibility analysis. Nat. Genet. 53, 403–411 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Leave a Comment