Multiple, Distant Gata2 Enhancers Specify Temporally and Tissue-specific Patterning in the Developing Urogenital System

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2004 Nov 16

PMID 15542836

Citations 32

Authors

Melin Khandekar

Norio Suzuki

Jon Lewton

Masayuki Yamamoto

James Douglas Engel

Affiliations

Soon will be listed here.

Abstract

Transcription factor GATA-2 is expressed in a complex temporally and tissue-specific pattern within the developing embryo. Loss-of-function studies in the mouse showed that GATA-2 activity is first required during very early hematopoiesis. We subsequently showed that a 271-kbp yeast artificial chromosome (YAC) transgene could fully complement the loss of Gata2 hematopoietic function but that these YAC-rescued Gata2 null mutant mice die perinatally due to defective urogenital development. The rescuing YAC did not display appropriate urogenital expression of Gata2, implying the existence of a urogenital-specific enhancer(s) lying outside the boundaries of this transgene. Here we outline a coupled general strategy for regulatory sequence discovery, linking bioinformatics to functional genomics based on the bacterial artificial chromosome (BAC) libraries used to generate the mouse genome sequence. Exploiting this strategy, we screened >1 Mbp of genomic DNA surrounding Gata2 for urogenital enhancer activity. We found that the spatially and tissue-specific functions for Gata2 in the developing urogenital system are conferred by at least three separate regionally and temporally specific urogenital enhancer elements, two of which reside far 3' to the Gata2 structural gene. Including the additional enhancers that were discovered using this strategy (called BAC trap) extends the functional realm of the Gata2 locus to greater than 1 Mbp.

Citing Articles

Integrative analysis of the ST6GALNAC family identifies GATA2-upregulated ST6GALNAC5 as an adverse prognostic biomarker promoting prostate cancer cell invasion.

Li M, Ma Z, Zhang Y, Feng H, Li Y, Sang W Cancer Cell Int. 2023; 23(1):141.

PMID: 37468844 PMC: 10355028. DOI: 10.1186/s12935-023-02983-x.

Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

Tenney A, Di Gioia S, Webb B, Chan W, de Boer E, Garnai S Nat Genet. 2023; 55(7):1149-1163.

PMID: 37386251 PMC: 10335940. DOI: 10.1038/s41588-023-01424-9.

heterozygous mutant mice exhibit reduced inflammatory responses and impaired bacterial clearance.

Takai J, Shimada T, Nakamura T, Engel J, Moriguchi T iScience. 2021; 24(8):102836.

PMID: 34471858 PMC: 8390858. DOI: 10.1016/j.isci.2021.102836.

Development and Carcinogenesis: Roles of GATA Factors in the Sympathoadrenal and Urogenital Systems.

Moriguchi T Biomedicines. 2021; 9(3).

PMID: 33803938 PMC: 8001475. DOI: 10.3390/biomedicines9030299.

A Novel GATA2 Protein Reporter Mouse Reveals Hematopoietic Progenitor Cell Types.

Ahmed N, Kunz L, Hoppe P, Loeffler D, Etzrodt M, Camargo Ortega G Stem Cell Reports. 2020; 15(2):326-339.

PMID: 32649900 PMC: 7419669. DOI: 10.1016/j.stemcr.2020.06.008.

References

Nishimura S, Takahashi S, Kuroha T, Suwabe N, Nagasawa T, Trainor C . A GATA box in the GATA-1 gene hematopoietic enhancer is a critical element in the network of GATA factors and sites that regulate this gene. Mol Cell Biol. 1999; 20(2):713-23. PMC: 85182. DOI: 10.1128/MCB.20.2.713-723.2000. View

Frengen E, Weichenhan D, Zhao B, Osoegawa K, van Geel M, de Jong P . A modular, positive selection bacterial artificial chromosome vector with multiple cloning sites. Genomics. 1999; 58(3):250-3. DOI: 10.1006/geno.1998.5693. View

DiLeone R, Marcus G, Johnson M, Kingsley D . Efficient studies of long-distance Bmp5 gene regulation using bacterial artificial chromosomes. Proc Natl Acad Sci U S A. 2000; 97(4):1612-7. PMC: 26483. DOI: 10.1073/pnas.97.4.1612. View

Loots G, Locksley R, Blankespoor C, Wang Z, Miller W, Rubin E . Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science. 2001; 288(5463):136-40. DOI: 10.1126/science.288.5463.136. View

Schwartz S, Zhang Z, Frazer K, Smit A, Riemer C, Bouck J . PipMaker--a web server for aligning two genomic DNA sequences. Genome Res. 2000; 10(4):577-86. PMC: 310868. DOI: 10.1101/gr.10.4.577. View

Yu D, Ellis H, Lee E, Jenkins N, Copeland N, Court D . An efficient recombination system for chromosome engineering in Escherichia coli. Proc Natl Acad Sci U S A. 2000; 97(11):5978-83. PMC: 18544. DOI: 10.1073/pnas.100127597. View

Lim K, Lakshmanan G, Crawford S, Gu Y, Grosveld F, Engel J . Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system. Nat Genet. 2000; 25(2):209-12. DOI: 10.1038/76080. View

Molkentin J, Tymitz K, Richardson J, Olson E . Abnormalities of the genitourinary tract in female mice lacking GATA5. Mol Cell Biol. 2000; 20(14):5256-60. PMC: 85974. DOI: 10.1128/MCB.20.14.5256-5260.2000. View

Zhou Y, Yamamoto M, Engel J . GATA2 is required for the generation of V2 interneurons. Development. 2000; 127(17):3829-38. DOI: 10.1242/dev.127.17.3829. View

10.

Bishop C, Whitworth D, Qin Y, Agoulnik A, Agoulnik I, HARRISON W . A transgenic insertion upstream of sox9 is associated with dominant XX sex reversal in the mouse. Nat Genet. 2000; 26(4):490-4. DOI: 10.1038/82652. View

11.

Lee E, Yu D, Martinez De Velasco J, Tessarollo L, Swing D, Court D . A highly efficient Escherichia coli-based chromosome engineering system adapted for recombinogenic targeting and subcloning of BAC DNA. Genomics. 2001; 73(1):56-65. DOI: 10.1006/geno.2000.6451. View

12.

Lettice L, Horikoshi T, Heaney S, van Baren M, der Linde H, Breedveld G . Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc Natl Acad Sci U S A. 2002; 99(11):7548-53. PMC: 124279. DOI: 10.1073/pnas.112212199. View

13.

Kitajima K, Masuhara M, Era T, Enver T, Nakano T . GATA-2 and GATA-2/ER display opposing activities in the development and differentiation of blood progenitors. EMBO J. 2002; 21(12):3060-9. PMC: 126056. DOI: 10.1093/emboj/cdf301. View

14.

Gregory S, Sekhon M, Schein J, Zhao S, Osoegawa K, Scott C . A physical map of the mouse genome. Nature. 2002; 418(6899):743-50. DOI: 10.1038/nature00957. View

15.

Vermeren M, Maro G, Bron R, McGonnell I, Charnay P, Topilko P . Integrity of developing spinal motor columns is regulated by neural crest derivatives at motor exit points. Neuron. 2003; 37(3):403-15. DOI: 10.1016/s0896-6273(02)01188-1. View

16.

Mortlock D, Guenther C, Kingsley D . A general approach for identifying distant regulatory elements applied to the Gdf6 gene. Genome Res. 2003; 13(9):2069-81. PMC: 403689. DOI: 10.1101/gr.1306003. View

17.

Nobrega M, Ovcharenko I, Afzal V, Rubin E . Scanning human gene deserts for long-range enhancers. Science. 2003; 302(5644):413. DOI: 10.1126/science.1088328. View

18.

Cawley S, Bekiranov S, Ng H, Kapranov P, Sekinger E, Kampa D . Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell. 2004; 116(4):499-509. DOI: 10.1016/s0092-8674(04)00127-8. View

19.

Marcantonio E, Grebenau R, Sabatini D, Kreibich G . Identification of ribophorins in rough microsomal membranes from different organs of several species. Eur J Biochem. 1982; 124(1):217-22. DOI: 10.1111/j.1432-1033.1982.tb05928.x. View

20.

Weber F, De Villiers J, Schaffner W . An SV40 "enhancer trap" incorporates exogenous enhancers or generates enhancers from its own sequences. Cell. 1984; 36(4):983-92. DOI: 10.1016/0092-8674(84)90048-5. View