The H3K4 methyltransferase Setd1b is essential for hematopoietic stem and progenitor cell homeostasis in mice

Hematopoietic stem cells require MLL1, which is one of six Set1/Trithorax-type histone 3 lysine 4 (H3K4) methyltransferases in mammals and clinically the most important leukemia gene. Here, we add to emerging evidence that all six H3K4 methyltransferases play essential roles in the hematopoietic system by showing that conditional mutagenesis of Setd1b in adult mice provoked aberrant homeostasis of hematopoietic stem and progenitor cells (HSPCs). Using both ubiquitous and hematopoietic-specific deletion strategies, the loss of Setd1b resulted in peripheral thrombo- and lymphocytopenia, multilineage dysplasia, myeloid-biased extramedullary hematopoiesis in the spleen, and lethality. By transplantation experiments and expression profiling, we determined that Setd1b is autonomously required in the hematopoietic lineages where it regulates key lineage specification components, including Cebpa, Gata1, and Klf1. Altogether, these data imply that the Set1/Trithorax-type epigenetic machinery sustains different aspects of hematopoiesis and constitutes a second framework additional to the transcription factor hierarchy of hematopoietic homeostasis.

[1]  I. Beerman.  Set(d1a)-ing novel links between HSC regulators. , 2018, Blood.

[2]  A. F. Stewart,et al.  SETD1A protects HSCs from activation-induced functional decline in vivo. , 2018, Blood.

[3]  T. Ogata,et al.  De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism , 2018, Human Genetics.

[4]  A. F. Stewart,et al.  Setd1b, encoding a histone 3 lysine 4 methyltransferase, is a maternal effect gene required for the oogenic gene expression program , 2017, Development.

[5]  E. Clappier,et al.  The MLL recombinome of acute leukemias in 2017 , 2017, Leukemia.

[6]  Kenneth L. Jones,et al.  MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia. , 2017, Cancer cell.

[7]  D. Bodine.  Introduction to the review series on transcription factors in hematopoiesis and hematologic disease. , 2017, Blood.

[8]  X. Matías-Guiu,et al.  Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma , 2017, International journal of cancer.

[9]  Hao Jiang,et al.  Dpy30 is critical for maintaining the identity and function of adult hematopoietic stem cells , 2016, The Journal of experimental medicine.

[10]  Cheol‐Hee Kim,et al.  An atypical 12q24.31 microdeletion implicates six genes including a histone demethylase KDM2B and a histone methyltransferase SETD1B in syndromic intellectual disability , 2016, Human Genetics.

[11]  L. Scott,et al.  Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research. , 2015, Blood.

[12]  Tariq Enver,et al.  Primed and ready: understanding lineage commitment through single cell analysis. , 2015, Trends in cell biology.

[13]  D. Baltimore,et al.  Regulation of stress-induced hematopoiesis , 2015, Current opinion in hematology.

[14]  Derrick J. Rossi,et al.  Epigenetic Control of Stem Cell Potential during Homeostasis, Aging, and Disease. , 2015, Cell stem cell.

[15]  J. Jesneck,et al.  Ott1 (Rbm15) regulates thrombopoietin response in hematopoietic stem cells through alternative splicing of c-Mpl. , 2015, Blood.

[16]  M. Carella,et al.  Microdeletion of 12q24.31: Report of a girl with intellectual disability, stereotypies, seizures and facial dysmorphisms , 2015, American journal of medical genetics. Part A.

[17]  T. Kitamura,et al.  The molecular basis of myeloid malignancies , 2014, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[18]  Ryan M. O’Connell,et al.  Conversion of Danger Signals into Cytokine Signals By Hematopoietic Stem and Progenitor Cells for Regulation of Stress-Induced Hematopoiesis , 2014 .

[19]  H. HogenEsch,et al.  The Epigenetic Regulator CXXC Finger Protein 1 is Essential for Murine Hematopoiesis , 2014, PloS one.

[20]  P. Ernst,et al.  Two decades of leukemia oncoprotein epistasis: the MLL1 paradigm for epigenetic deregulation in leukemia. , 2014, Experimental hematology.

[21]  Y. Chung,et al.  Frameshift mutation of a histone methylation-related gene SETD1B and its regional heterogeneity in gastric and colorectal cancers with high microsatellite instability. , 2014, Human pathology.

[22]  Scott A. Armstrong,et al.  DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier , 2014, Nature.

[23]  Ryan M. O’Connell,et al.  Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. , 2014, Cell stem cell.

[24]  A. Vannucchi,et al.  Complex karyotype in a polycythemia vera patient with a novel SETD1B/GTF2H3 fusion gene , 2014, American journal of hematology.

[25]  Qiang Feng,et al.  Identification of genomic alterations in oesophageal squamous cell cancer , 2014, Nature.

[26]  A. F. Stewart,et al.  The H3K4 methyltransferase Setd1a is first required at the epiblast stage, whereas Setd1b becomes essential after gastrulation , 2014, Development.

[27]  Weiqun Peng,et al.  H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation , 2013, eLife.

[28]  A. Moore,et al.  An MLL-dependent network sustains hematopoiesis , 2013, Proceedings of the National Academy of Sciences.

[29]  Wei Shi,et al.  featureCounts: an efficient general purpose program for assigning sequence reads to genomic features , 2013, Bioinform..

[30]  A. H. Smits,et al.  Quantitative Dissection and Stoichiometry Determination of the Human SET1/MLL Histone Methyltransferase Complexes , 2013, Molecular and Cellular Biology.

[31]  Alexander S. Garruss,et al.  Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. , 2012, Genes & development.

[32]  Jeong-Heon Lee,et al.  Rbm15-Mkl1 Interacts with the Setd1b Histone H3-Lys4 Methyltransferase via a SPOC Domain That Is Required for Cytokine-Independent Proliferation , 2012, PloS one.

[33]  A. Shilatifard.  The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. , 2012, Annual review of biochemistry.

[34]  M. Diaz,et al.  Histone recognition and nuclear receptor co-activator functions of Drosophila Cara Mitad, a homolog of the N-terminal portion of mammalian MLL2 and MLL3 , 2012, Development.

[35]  Dana E. Cullen,et al.  Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress. , 2012, Blood.

[36]  C. Vakoc,et al.  WRAD: enabler of the SET1-family of H3K4 methyltransferases. , 2012, Briefings in functional genomics.

[37]  Chris Williams,et al.  RNA-SeQC: RNA-seq metrics for quality control and process optimization , 2012, Bioinform..

[38]  E. Greer,et al.  Histone methylation: a dynamic mark in health, disease and inheritance , 2012, Nature Reviews Genetics.

[39]  Elinore M Mercer,et al.  Multilineage priming of enhancer repertoires precedes commitment to the B and myeloid cell lineages in hematopoietic progenitors. , 2011, Immunity.

[40]  A. Shilatifard,et al.  The COMPASS Family of H3K4 Methylases in Drosophila , 2011, Molecular and Cellular Biology.

[41]  Howard Cedar,et al.  Epigenetics of haematopoietic cell development , 2011, Nature Reviews Immunology.

[42]  M. Esteller,et al.  Epigenetic modifications and human disease , 2010, Nature Biotechnology.

[43]  Ronald Naumann,et al.  An improved Flp deleter mouse in C57Bl/6 based on Flpo recombinase , 2010, Genesis.

[44]  Martin M. Matzuk,et al.  MLL2 Is Required in Oocytes for Bulk Histone 3 Lysine 4 Trimethylation and Transcriptional Silencing , 2010, PLoS biology.

[45]  W. Huber,et al.  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets , 2011 .

[46]  Serban Nacu,et al.  Fast and SNP-tolerant detection of complex variants and splicing in short reads , 2010, Bioinform..

[47]  G. Pavlakis,et al.  Nuclear export factor RBM15 facilitates the access of DBP5 to mRNA , 2009, Nucleic acids research.

[48]  C. Niu,et al.  c-Myc is a target of RNA-binding motif protein 15 in the regulation of adult hematopoietic stem cell and megakaryocyte development. , 2009, Blood.

[49]  Frank Buchholz,et al.  Dre recombinase, like Cre, is a highly efficient site-specific recombinase in E. coli, mammalian cells and mice , 2009, Disease Models & Mechanisms.

[50]  Madelaine Gogol,et al.  Global Analysis of H3K4 Methylation Defines MLL Family Member Targets and Points to a Role for MLL1-Mediated H3K4 Methylation in the Regulation of Transcriptional Initiation by RNA Polymerase II , 2009, Molecular and Cellular Biology.

[51]  C. Bloomfield,et al.  The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. , 2009, Blood.

[52]  A. F. Stewart,et al.  The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis , 2009, Epigenetics & Chromatin.

[53]  S. Luc,et al.  Delineating the cellular pathways of hematopoietic lineage commitment. , 2008, Seminars in immunology.

[54]  K. Akashi,et al.  Reciprocal activation of GATA-1 and PU.1 marks initial specification of hematopoietic stem cells into myeloerythroid and myelolymphoid lineages. , 2007, Cell stem cell.

[55]  J. Fisher,et al.  Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. , 2007, Cell stem cell.

[56]  Shamit Soneji,et al.  Molecular evidence for hierarchical transcriptional lineage priming in fetal and adult stem cells and multipotent progenitors. , 2007, Immunity.

[57]  K. Akashi,et al.  Ott1(Rbm15) has pleiotropic roles in hematopoietic development , 2007, Proceedings of the National Academy of Sciences.

[58]  A. Fisher,et al.  Epigenetic signatures of stem-cell identity , 2007, Nature Reviews Genetics.

[59]  Nathaniel D. Heintzman,et al.  Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome , 2007, Nature Genetics.

[60]  M. Minden,et al.  Myelodysplastic syndromes: the complexity of stem-cell diseases , 2007, Nature Reviews Cancer.

[61]  C. Allis,et al.  Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. , 2007, Molecular cell.

[62]  Thomas A Milne,et al.  Regulation of MLL1 H3K4 methyltransferase activity by its core components , 2006, Nature Structural &Molecular Biology.

[63]  M. D. Boer,et al.  The MLL recombinome of acute leukemias , 2006, Leukemia.

[64]  A. F. Stewart,et al.  Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development , 2006, Development.

[65]  D. Skalnik,et al.  CpG-binding Protein (CXXC Finger Protein 1) Is a Component of the Mammalian Set1 Histone H3-Lys4 Methyltransferase Complex, the Analogue of the Yeast Set1/COMPASS Complex* , 2005, Journal of Biological Chemistry.

[66]  Thomas D. Wu,et al.  GMAP: a genomic mapping and alignment program for mRNA and EST sequence , 2005, Bioinform..

[67]  Lina A. Thoren,et al.  Identification of Flt3+ Lympho-Myeloid Stem Cells Lacking Erythro-Megakaryocytic Potential A Revised Road Map for Adult Blood Lineage Commitment , 2005, Cell.

[68]  Eric S. Lander,et al.  Genomic Maps and Comparative Analysis of Histone Modifications in Human and Mouse , 2005, Cell.

[69]  T. Graf,et al.  Assessing the role of hematopoietic plasticity for endothelial and hepatocyte development by non-invasive lineage tracing , 2004, Development.

[70]  A. Stewart,et al.  A reliable lacZ expression reporter cassette for multipurpose, knockout‐first alleles , 2004, Genesis.

[71]  S. Korsmeyer,et al.  Definitive hematopoiesis requires the mixed-lineage leukemia gene. , 2004, Developmental cell.

[72]  Rudolf Jaenisch,et al.  Rapid generation of inducible mouse mutants. , 2003, Nucleic acids research.

[73]  Thomas A Milne,et al.  MLL targets SET domain methyltransferase activity to Hox gene promoters. , 2002, Molecular cell.

[74]  Stuart L. Schreiber,et al.  Active genes are tri-methylated at K4 of histone H3 , 2002, Nature.

[75]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing , 2002, Science.

[76]  J. Downing,et al.  Bethesda proposals for classification of nonlymphoid hematopoietic neoplasms in mice. , 2002, Blood.

[77]  T. Graf.  Differentiation plasticity of hematopoietic cells. , 2002, Blood.

[78]  Rein Aasland,et al.  The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4 , 2001, The EMBO journal.

[79]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[80]  I. Weissman,et al.  Flk-2 is a marker in hematopoietic stem cell differentiation: A simple method to isolate long-term stem cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[81]  S. Jacobsen,et al.  Upregulation of Flt3 expression within the bone marrow Lin(-)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity. , 2001, Immunity.

[82]  I. Weissman,et al.  A clonogenic common myeloid progenitor that gives rise to all myeloid lineages , 2000, Nature.

[83]  A. W. Harris,et al.  Promoter elements of vav drive transgene expression in vivo throughout the hematopoietic compartment. , 1999, Blood.

[84]  T. Komori,et al.  Growth disturbance in fetal liver hematopoiesis of Mll-mutant mice. , 1998, Blood.

[85]  M. Cleary,et al.  Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX–ENL , 1997, The EMBO journal.

[86]  Hiromitsu Nakauchi,et al.  Long-Term Lymphohematopoietic Reconstitution by a Single CD34-Low/Negative Hematopoietic Stem Cell , 1996, Science.

[87]  C. Logie,et al.  Ligand-regulated site-specific recombination. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[88]  J. Rowley,et al.  Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[89]  I. Weissman,et al.  Purification and characterization of mouse hematopoietic stem cells. , 1988, Science.

[90]  Weiwei Yang,et al.  SET/MLL family proteins in hematopoiesis and leukemia , 2016, International Journal of Hematology.

[91]  Dpy 30 is critical for maintaining the identity and function of adult hematopoietic stem cells , 2016 .

[92]  D. Dale.  Intersections of hematology, immunology, dermatology and infectious diseases. , 2015, Current opinion in hematology.

[93]  Alexander S. Garruss,et al.  Enhancer-associated H 3 K 4 monomethylation by Trithorax-related , the Drosophila homolog of mammalian Mll 3 / Mll 4 , 2012 .

[94]  A. F. Stewart,et al.  A practical summary of site-specific recombination, conditional mutagenesis, and tamoxifen induction of CreERT2. , 2010, Methods in enzymology.

[95]  M. Krzywinski,et al.  New insights to the MLL recombinome of acute leukemias , 2009, Leukemia.

[96]  Tony Kouzarides,et al.  Histone H3 lysine 4 methylation patterns in higher eukaryotic genes , 2004, Nature Cell Biology.