SHORT COMMUNICATION A Cluster of Expressed Zinc Finger Protein Genes in the Pericentromeric Region of Human Chromosome 10 M. F. ROUSSEAU-MERCK,“,’

A. TuNNAcLIFFE,t

R. BERGER,* B. A. J. PONDER,t

AND

H. J. THIESEN+*

l /NSERM

U. 301 and SD/ 75954 I CNRS, Hdppital Saint-louis, Paris, France; tCRC Human Cancer Genetics Research Group, Department of Pathology, University of Cambridge, Cambridge, United Kingdom; and *Base/ Institute for Immunology, Base/, Switzerland Received

November

8, 1991;

revised

February

26, 1992

Kriippel zinc finger domains (14), originally cloned from cells of T cell origin (33). It was shown that two-thirds of all zinc finger genes are found near fragile sites (7, 28), and several zinc finger protein genes mapped to chromosomal regions that have been noted to be deleted or altered in neoplasms (7,14,27). Furthermore, the chromosomal distribution of the ZNF/KOX gene family on human chromosomes suggested the existence of zinc finger gene clusters (14). By means of in situ hybridization to metaphase chromosomes, evolutionarily conserved zinc finger gene complexes were identified on chromosome 17p13-p12 for ZNF18/KOXll and ZNF29/KOX26 (14, 27) and on chromosome 16q22 for ZNFlS/KOXl:! and ZNF23/KOX16 (7). By regional somatic cell hybrid analysis, an apparent clustering of KOX/ZNF loci was noted on chromosomes 7, 8, 10,17, and 19 (14). In particular, one zinc finger gene cluster was postulated to be located on chromosome region lOcen-q24 (14). Here, we report Academic Press, Inc. the regional mapping of ZNFll/KOXB, ZNF22/ KOX15, and ZNF25/KOX19 to the pericentromeric region of chromosome 10. The presence of numerous Kriippel-related zinc finger By somatic cell hybrid analysis (Fig. la) two humangenes (5, 22, 26, 32) in the mouse (8, 9) and human gespecific EcoRI bands of 4.0 and 1.75 kb (Fig. lb) were nomes (2,4,24) suggested that they might play a pivotal present in human control DNA as well as in somatic cell role in mammalian development and differentiation hybrid DNA of CY6, CZ, XTR, and 640-34~6 (21) after processes. An example is the zinc finger gene GL13 on hybridization with the KOX2 cDNA (33). Surprisingly, chromosome 7~13 (17), which is implicated in the etiolthe hybrid TG3 contained only the 4.0-kb fragment hyogy of the Greig cephalopolysyndactyly syndrome (34). bridizing to KOX2, whereas the KOX2 probe detected Deletions and/or mutations of zinc finger protein genes only the 1.75-kb fragment in hybrid TK2. These hybrids that control cell growth and/or differentiation processes carry reciprocal translocation chromosomes representmay also induce malignant transformations. Thus, the ing t(X;lO)(p22.3;qll.2), with lOpter-qll.2 present in WTl gene, which encodes a protein containing four zinc TG3 and lOqll.2qter in TK2. Thus, the KOX2 probe finger domains of the Ktippel type (6,12), is mutated in hybridized equally well to two different fragments lothe developmental syndrome Denys-Drash (25) as well cated on either side of the translocation breakpoint in as in Wilms tumors (6), where it behaves as a tumor band lOq11.2. By in situ hybridization to metaphase suppressor gene (18). Recently, we have been engaged in mapping 30 non- chromosomes, 250 mitoses were analyzed, with silver grain distribution showing a major cluster of 31 of 350 overlapping human cDNAs (cKOX l-30) encoding grains (8.8%) on chromosome lOpll-qll, including 23 grains (6.6% of the total count) on the centromere of chromosome 10 (Fig. 2a). Thus, the results obtained by 1 To whom all reprint requests should be addressed at INSERM U. in situ hybridization techniques suggest a localization 301, Institut de GBn&ique Molkulaire, 27 rue Juliette Dodu, 75010 for both ZNFll loci on chromosome lOcen-qll.2. ComParis. bining the somatic cell hybrid and in situ hybridization ’ To whom correspondence and probe requests should be addressed at Base1 Institute for Immunology, Grenzacherstrasse 487, CH-4005 data, the ZNFll/KOX:! locus can be separated at chroBasel. mosome region lOq11.2 into a proximal ZNFllA/ Three members of the human zinc finger Kriippel family, ZNFll/KOX2, ZNF22/KOX15, and ZNF25/ KOX19, have been regionally localized to the pericentromeric region of chromosome 10 by in situ chromosomal hybridization and somatic cell hybrid analysis. ZNF25/KOX19 is located centromeric to a breakpoint in chromosome band lOq11.2 in the chromosome region lOp11.2-q11.2, whereas ZNF22/KOX15 maps distal to it in band lOq11.2. Sequences hybridizing to the KOX2 probe are found at two loci, ZNFllA and ZNFl lB, that map proximal and distal to the lOqll.2 breakpoint, respectively. The two ZNFl 1 loci probably represent two related sequences in lOp11.2-q11.2. This cluster of ZNF/KOX genes is of particular interest since the loci for multiple endocrine neoplasia type 2A and 2B (MENBA and MENSB) syndromes have been assigned to this region by linkage analysis. 0 1992

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osas-7543/92 $5.00 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form resewed.

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FIG. 1. Localization of human zinc finger genes ZNFll/KOX2,ZNF22/KOX15, and ZNF25/KOX19 on chromosome 10 using a panel of somatic cell hybrids illustrated in a. The extent of human chromosome lo-specific DNA is indicated by a vertical bar. TG3 contains lOpterq11.2; TK2 has lOqll.2-qter (the reciprocal of TG3); CY6 has lOpter-q24; 64034~6 has lOpll.2-qter; CZ has a deletion of lOq21 and part of each adjacent band; XTR has 19pter-q23. (20). Cell hybrid 998-8 contains a human Y chromosome (11). (b) Two KOX2specific EcoRI bands of 4.0 and 1.75 kb are separated by the translocation breakpoint in lOq11.2 present in the TG3 and TK2 hybrids. (c) The ZNF22/KOX15 probe showed a single 4.7.kb human-specific band distal to the translocation breakpoint lOq11.2. (d) The ZNF25/KOX19 probe shows two humanspecific bands of 3.8 and 2.5 kb mapping proximal to the translocation breakpoint lOq11.2.

KOXBA locus (lOp11.2-q11.2) and a distal ZNFllB/ KOX2B locus (10q11.2). A single EcoRI 4.7-kb human-specific band was detected in the human control DNA after hybridization with the ZNF22/KOX15 cDNA (33). This band was present in every somatic cell hybrid except TG3 (Fig. lc), suggesting a location of the ZNF22/KOX15 gene distal to the breakpoint in band 10q11.2. In situ hybridization analysis demonstrated that ZNF22/KOX15 maps to lOq11.2. Among 188 metaphases analyzed, 25 of 245 grains (10.2%) were localized on chromosome region lOcen-q21 and 7.7% on chromosome region lOcen-qll

(Fig. 2b). A rather high background was noticed on chromosomes 17 (6.9% of the total count) and 19 (6.1% of the total count) but without further specific secondary signals. ZNF22/KOX15 can therefore be assigned to chromosome band lOq11.2. Recently, a genomic sequence encoding ZNF22/KOX15 was identified and mapped to chromosome region lOcen-qll.2 (4), and our data therefore confirm and extend this result. By hybridizing the ZNF25/KOX19 probe (33) to DNA of the somatic cell hybrid panel, two human-specific EcoRI fragments of 3.8 and 2.5 kb were detected in all hybrids that carry the chromosome region lOp11.2-

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b

a P

IS --a1,

P O"

10

10

In situ hybridization probe (a), with

KOX 19

KOX 15

KO‘X 2 FIG. 2. ZNFll/KOXZ

10

to metaphase the ZNF22/KOX15

chromosomes (13, 27, 28). Regional distribution probe (b) and with the ZNF25/KOX19 probe

q11.2. (Fig. Id). Since hybrid TK2 does not show a positive hybridization signal, the ZNF25/KOX19 locus must be located proximal to the translocation breakpoint lOq11.2. By in situ hybridization to human metaphase chromosomes, 27 grains (10.4%) of 260 grains on 182 mitoses were detected at chromosome region lOpll-ten (Fig. 2~). Both mapping techniques therefore suggest an assignment of ZNF25/KOX19 to the pericentromeric region of chromosome 10 (lOp11.2-q11.2). In this study, the chromosomal localizations of KOX zinc finger genes ZNFll/KOXB, ZNF22/KOX15, and ZNF25/KOX19 were determined by means of in situ hybridizations to human metaphase chromosomes to be clustered at the pericentromeric region of chromosome lO.ZNF25/KOX19 maps proximal and ZNF22/KOX15 distal to the breakpoint present in hybrids TG3 and TK2, suggesting the following gene order: lOpter(ZNFllA, ZNF25)-(ZNFllB, ZNF22)-1Oqter. The pericentromeric region of chromosome 10 is of particular interest since it contains the genetic loci for the multiple endocrine neoplasia syndromes MEN 2A and MEN 2B (19, 22, 29). Both syndromes are characterized by medullary thyroid carcinoma, pheochromocytoma, and autosomal dominant inheritance, with MEN 2B also exhibiting mucosal neuromas. The RET proto-oncogene, which is overexpressed in neuroblastoma, has been mapped to this region in lOq11.2 (15). The amino-terminal sequences of RET contain a tandem repeat of a sequence that represents most of the consensus sequence of a “finger” structure (31). RET is activated by rearrangement in 12-25% of human papillary thyroid carcinomas (3) and may also be a candidate gene for the MEN 2 syndromes. Human zinc finger genes ZNFll/ KOX2,ZNF22/KOX15, and ZNF25/KOX19, therefore, will provide novel genetic markers to improve the resolution of the genetic map of the region containing the MENSA and MENBB loci. Since zinc finger motifs are thought to he derived from a common ancestral small DNA binding motif (21), it can be assumed that genomic clustering and spreading of zinc finger genes arose by gene duplication and translo-

of silver (c).

grains

on chromosome

10

with

the

cation events. Thus, the two ZNFll/KOXB loci might have evolved by unequal crossing over during human phylogeny. Since a highly conserved homologue has not been detected in hamster or mouse DNA for ZNFll/ KOX2, it is tempting to speculate that the gene duplication observed for ZNFll/KOX:! occurred late in primate evolution. Recently, comparative genomic analysis of zinc finger genes encoded by the mouse and human genomes suggested that putative zinc finger gene complexes are evolutionarily conserved between human chromosome region 17p13-p12 and the distal half of mouse chromosome 11 (1,14, 27), and between human chromosome region 16q22 and the 16q region of mouse chromosome 8 (7, 10). Mouse and hamster zinc finger homologues have been detected for ZNF22/KOX15 (Fig. lc) and ZNF25/KOX19 (Fig. Id). The comparative analysis of evolutionarily conserved zinc finger gene clusters may be informative in determining the function of the corresponding proteins and in searching for common features of chromosomal structure and transcriptional regulation previously described for homeobox (30) and globin gene clusters (16). ACKNOWLEDGMENTS We thank Mrs H. Steingruber for providing somatic DNAs. The in situ hybridization analysis was supported Grant 6541 from ARC (Association pour la Recherche sur B.A.J.P. is a Gibb Fellow of the Cancer Research Campaign. se1 Institute for Immunology was founded and is supported man-LaRoche & Co., Ltd., Basel.

cell hybrid in part by le Cancer). The Baby F. Hoff-

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genes T cells.

encoding zinc finger New Bial. 2: 363-374.

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GL13 syn-

A cluster of expressed zinc finger protein genes in the pericentromeric region of human chromosome 10.

Three members of the human zinc finger Krüppel family, ZNF11/KOX2, ZNF22/KOX15, and ZNF25/KOX19, have been regionally localized to the pericentromeric...
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