The H3K4 Methyltransferase Setd1b is Essential for Hematopoietic Stem and Progenitor Cell Homeostasis in Mice

Overview

Journal Elife

Specialty Biology

Date 2018 Jun 20

PMID 29916805

Citations 21

Authors

Kerstin Schmidt

Qinyu Zhang

Alpaslan Tasdogan

Andreas Petzold

Andreas Dahl

Borros M Arneth

Robert Slany

Hans Jorg Fehling

Andrea Kranz

Adrian Francis Stewart

Konstantinos Anastassiadis

Affiliations

Soon will be listed here.

Abstract

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 , and . 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.

Citing Articles

MLL1 promotes placental trophoblast ferroptosis and aggravates preeclampsia symptoms through epigenetic regulation of RBM15/TRIM72/ADAM9 axis.

Li L, He H, Zheng Z, Zhao X Biol Direct. 2024; 19(1):133.

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SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma.

Portelinha A, Wang S, Parsa S, Jiang M, Gorelick A, Mohanty S J Exp Med. 2024; 221(10).

PMID: 39235528 PMC: 11380151. DOI: 10.1084/jem.20231143.

Epigenetic drug screening for trophoblast syncytialization reveals a novel role for MLL1 in regulating fetoplacental growth.

Wu J, Qin C, Tian F, Liu X, Hu J, Wu F BMC Med. 2024; 22(1):57.

PMID: 38317232 PMC: 10845764. DOI: 10.1186/s12916-024-03264-8.

KMT2 Family of H3K4 Methyltransferases: Enzymatic Activity-dependent and -independent Functions.

Van H, Xie G, Dong P, Liu Z, Ge K J Mol Biol. 2024; 436(7):168453.

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Noncoding rules of survival: epigenetic regulation of normal and malignant hematopoiesis.

Wallace L, Obeng E Front Mol Biosci. 2023; 10:1273046.

PMID: 38028538 PMC: 10644717. DOI: 10.3389/fmolb.2023.1273046.

References

Heintzman N, Stuart R, Hon G, Fu Y, Ching C, Hawkins R . Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet. 2007; 39(3):311-8. DOI: 10.1038/ng1966. View

Spangrude G, Heimfeld S, Weissman I . Purification and characterization of mouse hematopoietic stem cells. Science. 1988; 241(4861):58-62. DOI: 10.1126/science.2898810. View

Storlazzi C, Pieri L, Paoli C, Daniele G, Lasho T, Tefferi A . Complex karyotype in a polycythemia vera patient with a novel SETD1B/GTF2H3 fusion gene. Am J Hematol. 2014; 89(4):438-42. DOI: 10.1002/ajh.23659. View

Yang Z, Shah K, Khodadadi-Jamayran A, Jiang H . Dpy30 is critical for maintaining the identity and function of adult hematopoietic stem cells. J Exp Med. 2016; 213(11):2349-2364. PMC: 5068233. DOI: 10.1084/jem.20160185. View

Bledau A, Schmidt K, Neumann K, Hill U, Ciotta G, Gupta A . The H3K4 methyltransferase Setd1a is first required at the epiblast stage, whereas Setd1b becomes essential after gastrulation. Development. 2014; 141(5):1022-35. DOI: 10.1242/dev.098152. View

Herz H, Mohan M, Garruss A, Liang K, Takahashi Y, Mickey K . Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev. 2012; 26(23):2604-20. PMC: 3521626. DOI: 10.1101/gad.201327.112. View

Schneider R, Bannister A, Myers F, Thorne A, Crane-Robinson C, Kouzarides T . Histone H3 lysine 4 methylation patterns in higher eukaryotic genes. Nat Cell Biol. 2003; 6(1):73-7. DOI: 10.1038/ncb1076. View

Raffel G, Mercher T, Shigematsu H, Williams I, Cullen D, Akashi K . Ott1(Rbm15) has pleiotropic roles in hematopoietic development. Proc Natl Acad Sci U S A. 2007; 104(14):6001-6. PMC: 1851606. DOI: 10.1073/pnas.0609041104. View

Hiraide T, Nakashima M, Yamoto K, Fukuda T, Kato M, Ikeda H . De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism. Hum Genet. 2018; 137(1):95-104. DOI: 10.1007/s00439-017-1863-y. View

10.

Lee J, Skalnik D . 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. J Biol Chem. 2005; 280(50):41725-31. DOI: 10.1074/jbc.M508312200. View

11.

van Nuland R, Smits A, Pallaki P, Jansen P, Vermeulen M, Timmers H . Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexes. Mol Cell Biol. 2013; 33(10):2067-77. PMC: 3647974. DOI: 10.1128/MCB.01742-12. View

12.

Chauhan C, Zraly C, Parilla M, Diaz M, Dingwall A . Histone recognition and nuclear receptor co-activator functions of Drosophila cara mitad, a homolog of the N-terminal portion of mammalian MLL2 and MLL3. Development. 2012; 139(11):1997-2008. PMC: 3347691. DOI: 10.1242/dev.076687. View

13.

Chen Y, Anastassiadis K, Kranz A, Stewart A, Arndt K, Waskow C . MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia. Cancer Cell. 2017; 31(6):755-770.e6. PMC: 5598468. DOI: 10.1016/j.ccell.2017.05.002. View

14.

Portela A, Esteller M . Epigenetic modifications and human disease. Nat Biotechnol. 2010; 28(10):1057-68. DOI: 10.1038/nbt.1685. View

15.

Chun K, Li B, Dobrota E, Tate C, Lee J, Khan S . The epigenetic regulator CXXC finger protein 1 is essential for murine hematopoiesis. PLoS One. 2014; 9(12):e113745. PMC: 4254612. DOI: 10.1371/journal.pone.0113745. View

16.

Beerman I . Set(d1a)-ing novel links between HSC regulators. Blood. 2018; 131(12):1267-1269. PMC: 5865237. DOI: 10.1182/blood-2018-02-829077. View

17.

Ernst P, Fisher J, Avery W, Wade S, Foy D, Korsmeyer S . Definitive hematopoiesis requires the mixed-lineage leukemia gene. Dev Cell. 2004; 6(3):437-43. DOI: 10.1016/s1534-5807(04)00061-9. View

18.

Xiao N, Laha S, Das S, Morlock K, Jesneck J, Raffel G . Ott1 (Rbm15) regulates thrombopoietin response in hematopoietic stem cells through alternative splicing of c-Mpl. Blood. 2014; 125(6):941-8. PMC: 4319236. DOI: 10.1182/blood-2014-08-593392. View

19.

Arinobu Y, Mizuno S, Chong Y, Shigematsu H, Iino T, Iwasaki H . Reciprocal activation of GATA-1 and PU.1 marks initial specification of hematopoietic stem cells into myeloerythroid and myelolymphoid lineages. Cell Stem Cell. 2008; 1(4):416-27. DOI: 10.1016/j.stem.2007.07.004. View

20.

Brici D, Zhang Q, Reinhardt S, Dahl A, Hartmann H, Schmidt K . , encoding a histone 3 lysine 4 methyltransferase, is a maternal effect gene required for the oogenic gene expression program. Development. 2017; 144(14):2606-2617. DOI: 10.1242/dev.143347. View