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Am J Hum Genet. Sep 1999; 65(3): 699–708.
PMCID: PMC1377976

Polymorphic X-chromosome inactivation of the human TIMP1 gene.


X inactivation silences most but not all of the genes on one of the two X chromosomes in mammalian females. The human X chromosome preserves its activation status when isolated in rodent/human somatic-cell hybrids, and hybrids retaining either the active or inactive X chromosome have been used to assess the inactivation status of many X-linked genes. Surprisingly, the X-linked gene for human tissue inhibitor of metalloproteinases (TIMP1) is expressed in some but not all inactive X-containing somatic-cell hybrids, suggesting that this gene is either prone to reactivation or variable in its inactivation. Since many genes that escape X inactivation are clustered, we examined the expression of four genes (ARAF1, ELK1, ZNF41, and ZNF157) within approximately 100 kb of TIMP1. All four genes were expressed only from the active X chromosome, demonstrating that the factors allowing TIMP1 expression from the inactive X chromosome are specific to the TIMP1 gene. To determine if this variable inactivation of TIMP1 is a function of the hybrid-cell environment or also is observed in human cells, we developed an allele-specific assay to assess TIMP1 expression in human females. Expression of two alleles was detected in some female cells with previously demonstrated extreme skewing of X inactivation, indicating TIMP1 expression from the inactive chromosome. However, in other cells, no expression of TIMP1 was observed from the inactive X chromosome, suggesting that TIMP1 inactivation is polymorphic in human females.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 1992 Dec;51(6):1229–1239. [PMC free article] [PubMed]
  • Brandau O, Nyakatura G, Jedele KB, Platzer M, Achatz H, Ross M, Murken J, Rosenthal A, Meindl A. UHX1 and PCTK1: precise characterisation and localisation within a gene-rich region in Xp11.23 and evaluation as candidate genes for retinal diseases mapped to Xp21.1-p11.2. Eur J Hum Genet. 1998 Sep-Oct;6(5):459–466. [PubMed]
  • Brown CJ, Carrel L, Willard HF. Expression of genes from the human active and inactive X chromosomes. Am J Hum Genet. 1997 Jun;60(6):1333–1343. [PMC free article] [PubMed]
  • Brown CJ, Flenniken AM, Williams BR, Willard HF. X chromosome inactivation of the human TIMP gene. Nucleic Acids Res. 1990 Jul 25;18(14):4191–4195. [PMC free article] [PubMed]
  • Brown CJ, Hendrich BD, Rupert JL, Lafrenière RG, Xing Y, Lawrence J, Willard HF. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell. 1992 Oct 30;71(3):527–542. [PubMed]
  • Brown CJ, Lafreniere RG, Powers VE, Sebastio G, Ballabio A, Pettigrew AL, Ledbetter DH, Levy E, Craig IW, Willard HF. Localization of the X inactivation centre on the human X chromosome in Xq13. Nature. 1991 Jan 3;349(6304):82–84. [PubMed]
  • Brown CJ, Willard HF. Noninactivation of a selectable human X-linked gene that complements a murine temperature-sensitive cell cycle defect. Am J Hum Genet. 1989 Oct;45(4):592–598. [PMC free article] [PubMed]
  • Brown S, Rastan S. Age-related reactivation of an X-linked gene close to the inactivation centre in the mouse. Genet Res. 1988 Oct;52(2):151–154. [PubMed]
  • Carrel L, Hunt PA, Willard HF. Tissue and lineage-specific variation in inactive X chromosome expression of the murine Smcx gene. Hum Mol Genet. 1996 Sep;5(9):1361–1366. [PubMed]
  • Carrel L, Willard HF. An assay for X inactivation based on differential methylation at the fragile X locus, FMR1. Am J Med Genet. 1996 Jul 12;64(1):27–30. [PubMed]
  • Cattanach BM. Position effect variegation in the mouse. Genet Res. 1974 Jun;23(3):291–306. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Coleman MP, Németh AH, Campbell L, Raut CP, Weissenbach J, Davies KE. A 1.8-Mb YAC contig in Xp11.23: identification of CpG islands and physical mapping of CA repeats in a region of high gene density. Genomics. 1994 May 15;21(2):337–343. [PubMed]
  • Costanzi C, Pehrson JR. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature. 1998 Jun 11;393(6685):599–601. [PubMed]
  • Denhardt DT, Feng B, Edwards DR, Cocuzzi ET, Malyankar UM. Tissue inhibitor of metalloproteinases (TIMP, aka EPA): structure, control of expression and biological functions. Pharmacol Ther. 1993 Sep;59(3):329–341. [PubMed]
  • Derry JM, Barnard PJ. Physical linkage of the A-raf-1, properdin, synapsin I, and TIMP genes on the human and mouse X chromosomes. Genomics. 1992 Apr;12(4):632–638. [PubMed]
  • Derry JM, Jess U, Francke U. Cloning and characterization of a novel zinc finger gene in Xp11.2. Genomics. 1995 Nov 20;30(2):361–365. [PubMed]
  • Disteche CM. Escape from X inactivation in human and mouse. Trends Genet. 1995 Jan;11(1):17–22. [PubMed]
  • Duncan AM, Macdonald A, Brown CJ, Wolff D, Willard HF, Sutton B. Characterization of a small supernumerary ring X chromosome by fluorescence in situ hybridization. Am J Med Genet. 1993 Dec 1;47(8):1153–1156. [PubMed]
  • Ellis N, Keitges E, Gartler SM, Rocchi M. High-frequency reactivation of X-linked genes in Chinese hamster X human hybrid cells. Somat Cell Mol Genet. 1987 May;13(3):191–204. [PubMed]
  • Esposito T, Gianfrancesco F, Ciccodicola A, D'Esposito M, Nagaraja R, Mazzarella R, D'Urso M, Forabosco A. Escape from X inactivation of two new genes associated with DXS6974E and DXS7020E. Genomics. 1997 Jul 15;43(2):183–190. [PubMed]
  • Fisher EM, Beer-Romero P, Brown LG, Ridley A, McNeil JA, Lawrence JB, Willard HF, Bieber FR, Page DC. Homologous ribosomal protein genes on the human X and Y chromosomes: escape from X inactivation and possible implications for Turner syndrome. Cell. 1990 Dec 21;63(6):1205–1218. [PubMed]
  • Gartler SM, Goldman MA. Reactivation of inactive X-linked genes. Dev Genet. 1994;15(6):504–514. [PubMed]
  • Giannoukakis N, Deal C, Paquette J, Kukuvitis A, Polychronakos C. Polymorphic functional imprinting of the human IGF2 gene among individuals, in blood cells, is associated with H19 expression. Biochem Biophys Res Commun. 1996 Mar 27;220(3):1014–1019. [PubMed]
  • Gomez DE, Alonso DF, Yoshiji H, Thorgeirsson UP. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol. 1997 Oct;74(2):111–122. [PubMed]
  • Hansen RS, Ellis NA, Gartler SM. Demethylation of specific sites in the 5' region of the inactive X-linked human phosphoglycerate kinase gene correlates with the appearance of nuclease sensitivity and gene expression. Mol Cell Biol. 1988 Nov;8(11):4692–4699. [PMC free article] [PubMed]
  • Hardcastle AJ, Thiselton DL, Nayudu M, Hampson RM, Bhattacharya SS. Genomic organization of the human TIMP-1 gene. Investigation of a causative role in the pathogenesis of X-linked retinitis pigmentosa 2. Invest Ophthalmol Vis Sci. 1997 Aug;38(9):1893–1896. [PubMed]
  • Jeppesen P, Turner BM. The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression. Cell. 1993 Jul 30;74(2):281–289. [PubMed]
  • Jinno Y, Ikeda Y, Yun K, Maw M, Masuzaki H, Fukuda H, Inuzuka K, Fujishita A, Ohtani Y, Okimoto T, et al. Establishment of functional imprinting of the H19 gene in human developing placentae. Nat Genet. 1995 Jul;10(3):318–324. [PubMed]
  • Kahan B, DeMars R. Localized Derepression on the Human Inactive X Chromosone in Mouse-Human Cell Hybrids. Proc Natl Acad Sci U S A. 1975 Apr;72(4):1510–1514. [PMC free article] [PubMed]
  • Kaslow DC, Migeon BR. DNA methylation stabilizes X chromosome inactivation in eutherians but not in marsupials: evidence for multistep maintenance of mammalian X dosage compensation. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6210–6214. [PMC free article] [PubMed]
  • Knight JC, Grimaldi G, Thiesen HJ, Bech-Hansen NT, Fletcher CD, Coleman MP. Clustered organization of Krüppel zinc-finger genes at Xp11.23, flanking a translocation breakpoint at OATL1: a physical map with locus assignments for ZNF21, ZNF41, ZNF81, and ELK1. Genomics. 1994 May 1;21(1):180–187. [PubMed]
  • Leppig KA, Brown CJ, Bressler SL, Gustashaw K, Pagon RA, Willard HF, Disteche CM. Mapping of the distal boundary of the X-inactivation center in a rearranged X chromosome from a female expressing XIST. Hum Mol Genet. 1993 Jul;2(7):883–887. [PubMed]
  • Linder D, Gartler SM. Glucose-6-phosphate dehydrogenase mosaicism: utilization as a cell marker in the study of leiomyomas. Science. 1965 Oct 1;150(3692):67–69. [PubMed]
  • Lingenfelter PA, Adler DA, Poslinski D, Thomas S, Elliott RW, Chapman VM, Disteche CM. Escape from X inactivation of Smcx is preceded by silencing during mouse development. Nat Genet. 1998 Mar;18(3):212–213. [PubMed]
  • LYON MF. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature. 1961 Apr 22;190:372–373. [PubMed]
  • Migeon BR. Stability of X chromosomal inactivation in human somatic cells. Nature. 1972 Sep 8;239(5367):87–89. [PubMed]
  • Migeon BR, Axelman J, Beggs AH. Effect of ageing on reactivation of the human X-linked HPRT locus. Nature. 1988 Sep 1;335(6185):93–96. [PubMed]
  • Migeon BR, Axelman J, Stetten G. Clonal evolution in human lymphoblast cultures. Am J Hum Genet. 1988 May;42(5):742–747. [PMC free article] [PubMed]
  • Migeon BR, Shapiro LJ, Norum RA, Mohandas T, Axelman J, Dabora RL. Differential expression of steroid sulphatase locus on active and inactive human X chromosome. Nature. 1982 Oct 28;299(5886):838–840. [PubMed]
  • Migeon BR, Wolf SF, Axelman J, Kaslow DC, Schmidt M. Incomplete X chromosome dosage compensation in chorionic villi of human placenta. Proc Natl Acad Sci U S A. 1985 May;82(10):3390–3394. [PMC free article] [PubMed]
  • Miller AP, Willard HF. Chromosomal basis of X chromosome inactivation: identification of a multigene domain in Xp11.21-p11.22 that escapes X inactivation. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8709–8714. [PMC free article] [PubMed]
  • Ohlsson R, Hedborg F, Holmgren L, Walsh C, Ekström TJ. Overlapping patterns of IGF2 and H19 expression during human development: biallelic IGF2 expression correlates with a lack of H19 expression. Development. 1994 Feb;120(2):361–368. [PubMed]
  • Plenge RM, Hendrich BD, Schwartz C, Arena JF, Naumova A, Sapienza C, Winter RM, Willard HF. A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation. Nat Genet. 1997 Nov;17(3):353–356. [PubMed]
  • Rupert JL, Brown CJ, Willard HF. Direct detection of non-random X chromosome inactivation by use of a transcribed polymorphism in the XIST gene. Eur J Hum Genet. 1995;3(6):333–343. [PubMed]
  • Schempp W, Meer B. Cytologic evidence for three human X-chromosomal segments escaping inactivation. Hum Genet. 1983;63(2):171–174. [PubMed]
  • Schneider-Gädicke A, Beer-Romero P, Brown LG, Nussbaum R, Page DC. ZFX has a gene structure similar to ZFY, the putative human sex determinant, and escapes X inactivation. Cell. 1989 Jun 30;57(7):1247–1258. [PubMed]
  • Sheardown S, Norris D, Fisher A, Brockdorff N. The mouse Smcx gene exhibits developmental and tissue specific variation in degree of escape from X inactivation. Hum Mol Genet. 1996 Sep;5(9):1355–1360. [PubMed]
  • Wareham KA, Lyon MF, Glenister PH, Williams ED. Age related reactivation of an X-linked gene. Nature. 327(6124):725–727. [PubMed]
  • Willard HF, Brown CJ, Carrel L, Hendrich B, Miller AP. Epigenetic and chromosomal control of gene expression: molecular and genetic analysis of X chromosome inactivation. Cold Spring Harb Symp Quant Biol. 1993;58:315–322. [PubMed]
  • Yang-Feng TL, DeGennaro LJ, Francke U. Genes for synapsin I, a neuronal phosphoprotein, map to conserved regions of human and murine X chromosomes. Proc Natl Acad Sci U S A. 1986 Nov;83(22):8679–8683. [PMC free article] [PubMed]

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