Identification of Long-range Regulatory Elements in the Protocadherin-alpha Gene Cluster

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Dec 19

PMID 17172445

Citations 72

Authors

Scott Ribich

Bosiljka Tasic

Tom Maniatis

Affiliations

Soon will be listed here.

Abstract

The clustered protocadherins (Pcdh) are encoded by three closely linked gene clusters (Pcdh-alpha, -beta, and -gamma) that span nearly 1 million base pairs of DNA. The Pcdh-alpha gene cluster encodes a family of 14 distinct cadherin-like cell surface proteins that are expressed in neurons and are present at synaptic junctions. Individual Pcdh-alpha mRNAs are assembled from one of 14 "variable" (V) exons and three "constant" exons in a process that involves both differential promoter activation and alternative pre-mRNA splicing. In individual neurons, only one (and rarely two) of the Pcdh alpha1-12 promoters is independently and randomly activated on each chromosome. Thus, in most cells, this unusual form of monoallelic expression leads to the expression of two different Pcdh-alpha 1-12 V exons, one from each chromosome. The two remaining V exons in the cluster (Pcdh-alphaC1 and alphaC2) are expressed biallelically in every neuron. The mechanisms that underlie promoter choice and monoallelic expression in the Pcdh-alpha gene cluster are not understood. Here we report the identification of two long-range cis-regulatory elements in the Pcdh-alpha gene cluster, HS5-1 and HS7. We show that HS5-1 is required for maximal levels of expression from the Pcdh alpha1-12 and alphaC1 promoters, but not the Pcdh-alphaC2 promoter. The nearly cluster-wide requirement of the HS5-1 element is consistent with the possibility that the monoallelic expression of Pcdh-alpha V exons is a consequence of competition between individual V exon promoters for the two regulatory elements.

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References

Senzaki K, Ogawa M, Yagi T . Proteins of the CNR family are multiple receptors for Reelin. Cell. 1999; 99(6):635-47. DOI: 10.1016/s0092-8674(00)81552-4. View

Kothary R, Clapoff S, Darling S, Perry M, Moran L, Rossant J . Inducible expression of an hsp68-lacZ hybrid gene in transgenic mice. Development. 1989; 105(4):707-14. DOI: 10.1242/dev.105.4.707. 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

Rhoades K, Singh N, Simon I, Glidden B, Cedar H, Chess A . Allele-specific expression patterns of interleukin-2 and Pax-5 revealed by a sensitive single-cell RT-PCR analysis. Curr Biol. 2000; 10(13):789-92. DOI: 10.1016/s0960-9822(00)00565-0. View

Mayor C, Brudno M, Schwartz J, Poliakov A, Rubin E, Frazer K . VISTA : visualizing global DNA sequence alignments of arbitrary length. Bioinformatics. 2001; 16(11):1046-7. DOI: 10.1093/bioinformatics/16.11.1046. View

Wu Q, Zhang T, Cheng J, Kim Y, Grimwood J, Schmutz J . Comparative DNA sequence analysis of mouse and human protocadherin gene clusters. Genome Res. 2001; 11(3):389-404. PMC: 311048. DOI: 10.1101/gr.167301. View

Carroll P, Gayet O, Feuillet C, Kallenbach S, De Bovis B, Dudley K . Juxtaposition of CNR protocadherins and reelin expression in the developing spinal cord. Mol Cell Neurosci. 2001; 17(4):611-23. DOI: 10.1006/mcne.2001.0966. View

Eggan K, Akutsu H, Loring J, Klemm M, Rideout 3rd W, Yanagimachi R . Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation. Proc Natl Acad Sci U S A. 2001; 98(11):6209-14. PMC: 33447. DOI: 10.1073/pnas.101118898. View

Takei Y, Hamada S, Senzaki K, Mutoh T, Sugino H, Yagi T . Two novel CNRs from the CNR gene cluster have molecular features distinct from those of CNR1 to 8. Genomics. 2001; 72(3):321-30. DOI: 10.1006/geno.2000.6468. View

10.

Heymann R, Kallenbach S, Alonso S, Carroll P, Mitsiadis T . Dynamic expression patterns of the new protocadherin families CNRs and Pcdh-gamma during mouse odontogenesis: comparison with reelin expression. Mech Dev. 2001; 106(1-2):181-4. DOI: 10.1016/s0925-4773(01)00433-6. View

11.

Johnson K, Christensen H, Zhao B, Bresnick E . Distinct mechanisms control RNA polymerase II recruitment to a tissue-specific locus control region and a downstream promoter. Mol Cell. 2001; 8(2):465-71. DOI: 10.1016/s1097-2765(01)00309-4. View

12.

Bender M, Roach J, Halow J, Close J, Alami R, Bouhassira E . Targeted deletion of 5'HS1 and 5'HS4 of the beta-globin locus control region reveals additive activity of the DNaseI hypersensitive sites. Blood. 2001; 98(7):2022-7. DOI: 10.1182/blood.v98.7.2022. View

13.

Tasic B, Nabholz C, Baldwin K, Kim Y, Rueckert E, Ribich S . Promoter choice determines splice site selection in protocadherin alpha and gamma pre-mRNA splicing. Mol Cell. 2002; 10(1):21-33. DOI: 10.1016/s1097-2765(02)00578-6. View

14.

Wang X, Su H, Bradley A . Molecular mechanisms governing Pcdh-gamma gene expression: evidence for a multiple promoter and cis-alternative splicing model. Genes Dev. 2002; 16(15):1890-905. PMC: 186422. DOI: 10.1101/gad.1004802. View

15.

Frazer K, Elnitski L, Church D, Dubchak I, Hardison R . Cross-species sequence comparisons: a review of methods and available resources. Genome Res. 2003; 13(1):1-12. PMC: 430969. DOI: 10.1101/gr.222003. View

16.

Lee G, Fields P, Griffin T, Flavell R . Regulation of the Th2 cytokine locus by a locus control region. Immunity. 2003; 19(1):145-53. DOI: 10.1016/s1074-7613(03)00179-1. View

17.

Abe Y, Kouyama K, Tomita T, Tomita Y, Ban N, Nawa M . Analysis of neurons created from wild-type and Alzheimer's mutation knock-in embryonic stem cells by a highly efficient differentiation protocol. J Neurosci. 2003; 23(24):8513-25. PMC: 6740361. View

18.

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

19.

Visel A, Thaller C, Eichele G . GenePaint.org: an atlas of gene expression patterns in the mouse embryo. Nucleic Acids Res. 2003; 32(Database issue):D552-6. PMC: 308763. DOI: 10.1093/nar/gkh029. View

20.

Frazer K, Pachter L, Poliakov A, Rubin E, Dubchak I . VISTA: computational tools for comparative genomics. Nucleic Acids Res. 2004; 32(Web Server issue):W273-9. PMC: 441596. DOI: 10.1093/nar/gkh458. View