Polycomb Group Protein YY1 Is an Essential Regulator of Hematopoietic Stem Cell Quiescence

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2018 Feb 10

PMID 29425509

Citations 25

Authors

Zhanping Lu

Courtney C Hong

Guangyao Kong

Anna L F V Assumpcao

Irene M Ong

Emery H Bresnick

Jing Zhang

Xuan Pan

Affiliations

Soon will be listed here.

Abstract

Yin yang 1 (YY1) is a ubiquitous transcription factor and mammalian polycomb group protein (PcG) with important functions to regulate embryonic development, lineage differentiation, and cell proliferation. YY1 mediates stable PcG-dependent transcriptional repression via recruitment of PcG proteins that catalyze histone modifications. Many questions remain unanswered regarding how cell- and tissue-specificity is achieved by PcG proteins. Here, we demonstrate that a conditional knockout of Yy1 in hematopoietic stem cells (HSCs) decreases long-term repopulating activity and ectopic YY1 expression expands HSCs. Although the YY1 PcG domain is required for Igκ chain rearrangement in B cells, the YY1 mutant lacking the PcG domain retained the capacity to stimulate HSC self-renewal. YY1 deficiency deregulated the genetic network governing HSC cell proliferation and impaired stem cell factor/c-Kit signaling, disrupting mechanisms conferring HSC quiescence. These results reveal a mechanism for how a ubiquitously expressed transcriptional repressor mediates lineage-specific functions to control adult hematopoiesis.

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References

Chen L, Foreman D, SantAngelo D, Krangel M . Yin Yang 1 Promotes Thymocyte Survival by Downregulating p53. J Immunol. 2016; 196(6):2572-82. PMC: 4779672. DOI: 10.4049/jimmunol.1501916. View

Bushmeyer S, Park K, Atchison M . Characterization of functional domains within the multifunctional transcription factor, YY1. J Biol Chem. 1995; 270(50):30213-20. DOI: 10.1074/jbc.270.50.30213. View

Rizo A, Olthof S, Han L, Vellenga E, de Haan G, Schuringa J . Repression of BMI1 in normal and leukemic human CD34(+) cells impairs self-renewal and induces apoptosis. Blood. 2009; 114(8):1498-505. DOI: 10.1182/blood-2009-03-209734. View

Liu H, Schmidt-Supprian M, Shi Y, Hobeika E, Barteneva N, Jumaa H . Yin Yang 1 is a critical regulator of B-cell development. Genes Dev. 2007; 21(10):1179-89. PMC: 1865490. DOI: 10.1101/gad.1529307. View

Jing H, Vakoc C, Ying L, Mandat S, Wang H, Zheng X . Exchange of GATA factors mediates transitions in looped chromatin organization at a developmentally regulated gene locus. Mol Cell. 2008; 29(2):232-42. PMC: 2254447. DOI: 10.1016/j.molcel.2007.11.020. View

Wilkinson F, Park K, Atchison M . Polycomb recruitment to DNA in vivo by the YY1 REPO domain. Proc Natl Acad Sci U S A. 2006; 103(51):19296-301. PMC: 1748220. DOI: 10.1073/pnas.0603564103. View

Iwama A, Oguro H, Negishi M, Kato Y, Morita Y, Tsukui H . Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity. 2004; 21(6):843-51. DOI: 10.1016/j.immuni.2004.11.004. View

Kleiman E, Jia H, Loguercio S, Su A, Feeney A . YY1 plays an essential role at all stages of B-cell differentiation. Proc Natl Acad Sci U S A. 2016; 113(27):E3911-20. PMC: 4941496. DOI: 10.1073/pnas.1606297113. View

Majewski I, Ritchie M, Phipson B, Corbin J, Pakusch M, Ebert A . Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells. Blood. 2010; 116(5):731-9. DOI: 10.1182/blood-2009-12-260760. View

10.

Srinivasan L, Atchison M . YY1 DNA binding and PcG recruitment requires CtBP. Genes Dev. 2004; 18(21):2596-601. PMC: 525539. DOI: 10.1101/gad.1228204. View

11.

Wang L, Brown J, Cao R, Zhang Y, Kassis J, Jones R . Hierarchical recruitment of polycomb group silencing complexes. Mol Cell. 2004; 14(5):637-46. DOI: 10.1016/j.molcel.2004.05.009. View

12.

Hewitt K, Kim D, Devadas P, Prathibha R, Zuo C, Sanalkumar R . Hematopoietic Signaling Mechanism Revealed from a Stem/Progenitor Cell Cistrome. Mol Cell. 2015; 59(1):62-74. PMC: 4499333. DOI: 10.1016/j.molcel.2015.05.020. View

13.

Li J, Song J, Bell R, Tran T, Haq R, Liu H . YY1 regulates melanocyte development and function by cooperating with MITF. PLoS Genet. 2012; 8(5):e1002688. PMC: 3342948. DOI: 10.1371/journal.pgen.1002688. View

14.

Atchison L, Ghias A, Wilkinson F, Bonini N, Atchison M . Transcription factor YY1 functions as a PcG protein in vivo. EMBO J. 2003; 22(6):1347-58. PMC: 151054. DOI: 10.1093/emboj/cdg124. View

15.

Affar E, Gay F, Shi Y, Liu H, Huarte M, Wu S . Essential dosage-dependent functions of the transcription factor yin yang 1 in late embryonic development and cell cycle progression. Mol Cell Biol. 2006; 26(9):3565-81. PMC: 1447422. DOI: 10.1128/MCB.26.9.3565-3581.2006. View

16.

Pan X, Jones M, Jiang J, Zaprazna K, Yu D, Pear W . Increased expression of PcG protein YY1 negatively regulates B cell development while allowing accumulation of myeloid cells and LT-HSC cells. PLoS One. 2012; 7(1):e30656. PMC: 3264595. DOI: 10.1371/journal.pone.0030656. View

17.

Kamminga L, Bystrykh L, de Boer A, Houwer S, Douma J, Weersing E . The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood. 2005; 107(5):2170-9. PMC: 1895717. DOI: 10.1182/blood-2005-09-3585. View

18.

Srinivasan L, Pan X, Atchison M . Transient requirements of YY1 expression for PcG transcriptional repression and phenotypic rescue. J Cell Biochem. 2005; 96(4):689-99. DOI: 10.1002/jcb.20562. View

19.

Orford K, Scadden D . Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet. 2008; 9(2):115-28. DOI: 10.1038/nrg2269. View

20.

Wilson N, Foster S, Wang X, Knezevic K, Schutte J, Kaimakis P . Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators. Cell Stem Cell. 2010; 7(4):532-44. DOI: 10.1016/j.stem.2010.07.016. View