Genome-Wide Analysis Identifies and As Novel Notch1 Transcriptional Targets in Thymocytes

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2021 Jul 29

PMID 34322489

Citations 8

Authors

Yang Dong

Hao Guo

Donghai Wang

Rongfu Tu

Guoliang Qing

Hudan Liu

Affiliations

Soon will be listed here.

Abstract

Recombination activating genes 1 () and are expressed in immature lymphocytes and essential for generating the vast repertoire of antigen receptors. Yet, the mechanisms governing the transcription of and remain to be fully determined, particularly in thymocytes. Combining cDNA microarray and ChIP-seq analysis, we identify and as novel Notch1 transcriptional targets in acute T-cell lymphoblastic leukemia (T-ALL) cells. We further demonstrate that Notch1 transcriptional complexes directly bind the and locus in not only T-ALL but also primary double negative (DN) T-cell progenitors. Specifically, dimeric Notch1 transcriptional complexes activate and through a novel -element bearing a sequence-paired site (SPS). In T-ALL and DN cells, dimerization-defective Notch1 causes compromised and expression; conversely, dimerization-competent Notch1 achieves optimal upregulation of both. Collectively, these results reveal Notch1 dimerization-mediated transcription as one of the mechanisms for activating and expression in both primary and transformed thymocytes. Our data suggest a new role of Notch1 dimerization in compelling efficient TCRβ rearrangements in DN progenitors during T-cell development.

Citing Articles

T Cell Receptor Chain Centricity: The Phenomenon and Potential Applications in Cancer Immunotherapy.

Kalinina A, Khromykh L, Kazansky D Int J Mol Sci. 2023; 24(20).

PMID: 37894892 PMC: 10607890. DOI: 10.3390/ijms242015211.

SHIP1 Is Present but Strongly Downregulated in T-ALL, and after Restoration Suppresses Leukemia Growth in a T-ALL Xenotransplantation Mouse Model.

Ehm P, Rietow R, Wegner W, Bussmann L, Kriegs M, Dierck K Cells. 2023; 12(13).

PMID: 37443832 PMC: 10341211. DOI: 10.3390/cells12131798.

The initial age-associated decline in early T-cell progenitors reflects fewer pre-thymic progenitors and altered signals in the bone marrow and thymus microenvironments.

Srinivasan J, Vasudev A, Shasha C, Selden H, Perez Jr E, LaFleur B Aging Cell. 2023; 22(8):e13870.

PMID: 37221658 PMC: 10410006. DOI: 10.1111/acel.13870.

Established and Emerging Methods for Protecting Linear DNA in Cell-Free Expression Systems.

Fochtman T, Oza J Methods Protoc. 2023; 6(2).

PMID: 37104018 PMC: 10146267. DOI: 10.3390/mps6020036.

Lymphoid cell development from fetal hematopoietic progenitors and human pluripotent stem cells.

Sun S, Wijanarko K, Liani O, Strumila K, Ng E, Elefanty A Immunol Rev. 2023; 315(1):154-170.

PMID: 36939073 PMC: 10952469. DOI: 10.1111/imr.13197.

References

Searfoss G, Jordan W, Calligaro D, Galbreath E, Schirtzinger L, Berridge B . Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem. 2003; 278(46):46107-16. DOI: 10.1074/jbc.M307757200. View

Sambandam A, Maillard I, Zediak V, Xu L, Gerstein R, Aster J . Notch signaling controls the generation and differentiation of early T lineage progenitors. Nat Immunol. 2005; 6(7):663-70. DOI: 10.1038/ni1216. View

Miyazaki K, Watanabe H, Yoshikawa G, Chen K, Hidaka R, Aitani Y . The transcription factor E2A activates multiple enhancers that drive expression in developing T and B cells. Sci Immunol. 2020; 5(51). DOI: 10.1126/sciimmunol.abb1455. View

Weng A, Nam Y, Wolfe M, Pear W, Griffin J, Blacklow S . Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol. 2003; 23(2):655-64. PMC: 151540. DOI: 10.1128/MCB.23.2.655-664.2003. View

Campese A, Garbe A, Zhang F, Grassi F, Screpanti I, von Boehmer H . Notch1-dependent lymphomagenesis is assisted by but does not essentially require pre-TCR signaling. Blood. 2006; 108(1):305-10. PMC: 1895839. DOI: 10.1182/blood-2006-01-0143. View

MONROE R, Chen F, Ferrini R, Davidson L, Alt F . RAG2 is regulated differentially in B and T cells by elements 5' of the promoter. Proc Natl Acad Sci U S A. 1999; 96(22):12713-8. PMC: 23063. DOI: 10.1073/pnas.96.22.12713. View

Aplan P, Lombardi D, Reaman G, Sather H, Hammond G, Kirsch I . Involvement of the putative hematopoietic transcription factor SCL in T-cell acute lymphoblastic leukemia. Blood. 1992; 79(5):1327-33. View

Helmink B, Sleckman B . The response to and repair of RAG-mediated DNA double-strand breaks. Annu Rev Immunol. 2012; 30:175-202. PMC: 4038028. DOI: 10.1146/annurev-immunol-030409-101320. View

Wolfer A, Wilson A, Nemir M, MacDonald H, Radtke F . Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta Lineage Thymocytes. Immunity. 2002; 16(6):869-79. DOI: 10.1016/s1074-7613(02)00330-8. View

10.

Zhang Y, Gostissa M, Hildebrand D, Becker M, Boboila C, Chiarle R . The role of mechanistic factors in promoting chromosomal translocations found in lymphoid and other cancers. Adv Immunol. 2010; 106:93-133. PMC: 3073861. DOI: 10.1016/S0065-2776(10)06004-9. View

11.

Kourtis N, Lazaris C, Hockemeyer K, Balandran J, Jimenez A, Mullenders J . Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia. Nat Med. 2018; 24(8):1157-1166. PMC: 6082694. DOI: 10.1038/s41591-018-0105-8. View

12.

Zhang F, Thomas L, Oltz E, Aune T . Control of thymocyte development and recombination-activating gene expression by the zinc finger protein Zfp608. Nat Immunol. 2006; 7(12):1309-16. DOI: 10.1038/ni1397. View

13.

Arnett K, Hass M, McArthur D, Ilagan M, Aster J, Kopan R . Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes. Nat Struct Mol Biol. 2010; 17(11):1312-7. PMC: 3024583. DOI: 10.1038/nsmb.1938. View

14.

Pear W, Aster J, Scott M, Hasserjian R, Soffer B, Sklar J . Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med. 1996; 183(5):2283-91. PMC: 2192581. DOI: 10.1084/jem.183.5.2283. View

15.

Weng A, Ferrando A, Lee W, Morris 4th J, Silverman L, Sanchez-Irizarry C . Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004; 306(5694):269-71. DOI: 10.1126/science.1102160. View

16.

Wang H, Zou J, Zhao B, Johannsen E, Ashworth T, Wong H . Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells. Proc Natl Acad Sci U S A. 2011; 108(36):14908-13. PMC: 3169118. DOI: 10.1073/pnas.1109023108. View

17.

Wei X, Kishi H, Jin Z, Zhao W, Kondo S, Matsuda T . Characterization of chromatin structure and enhancer elements for murine recombination activating gene-2. J Immunol. 2002; 169(2):873-81. DOI: 10.4049/jimmunol.169.2.873. View

18.

Real P, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E . Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med. 2008; 15(1):50-8. PMC: 2692090. DOI: 10.1038/nm.1900. View

19.

Yu W, Misulovin Z, Suh H, Hardy R, Jankovic M, Yannoutsos N . Coordinate regulation of RAG1 and RAG2 by cell type-specific DNA elements 5' of RAG2. Science. 1999; 285(5430):1080-4. DOI: 10.1126/science.285.5430.1080. View

20.

Liu H, Chi A, Arnett K, Chiang M, Xu L, Shestova O . Notch dimerization is required for leukemogenesis and T-cell development. Genes Dev. 2010; 24(21):2395-407. PMC: 2964750. DOI: 10.1101/gad.1975210. View