Biopolym. Cell. 2009; 25(1):12-26.
Recombination in immunoglobulin gene loci
1Halytskiy V. A., 1Komisarenko S. V.
  1. Palladin Institute of Biochemistry, NAS of Ukraine
    9, Leontovycha Str., Kyiv, Ukraine, 01601


Gene network of the lymphoid cell differentiation coordinates precisely the recombination process in immunoglobulin gene loci. In our opinion, cellular microRNAs can contribute to the allelic exclusion through microRNA-directed DNA methylation and participate in retargeting recombinases activity from the gene loci of heavy immunoglobulin chains to the gene loci of light chains .
Keywords: immunoglobulin gene locus, recombination, microRNA, allelic exclusion


[1] Johnston C. M., Wood A. L., Bolland D. J., Corcoran A. E. Complete sequence assembly and characterization of the C57BL/6 mouse Ig heavy chain V region. J. Immunol. 2006; 176(7):4221–4234.
[2] Tonegawa S. Somatic generation of antibody diversity Nature 1983 302, N 5909:575–581.
[3] Jung D., Giallourakis C., Mostoslavsky R., Alt F. W. Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus Annu. Rev. Immunol 2006 24:541–570.
[4] Grundy G. J., Hesse J. E., Gellert M. Requirements for DNA hairpin formation by RAG1/2 Proc. Nat. Acad. Sci. USA 2007 104, N 9:3078–3083.
[5] Komori T., Sugiyama H. N sequences, P nucleotides and short sequence homologies at junctional sites in VH to VHDJH and VHDJH to JH joining Mol. Immunol 1993 30, N 16 P. 1393–1398.
[6] Jackson K. J., Gaeta B., Sewell W., Collins A. M. Exonuclease activity and P nucleotide addition in the generation of the expressed immunoglobulin repertoire BMC Immunol 2004 5:19.
[7] Rooney S., Chaudhuri J., Alt F. W. The role of the non-homologous end-joining pathway in lymphocyte development Immunol. Rev 2004 200:115–131.
[8] Sakano H., Huppi K., Heinrich G., Tonegawa S. Sequences at the somatic recombination sites of immunoglobulin lightchain genes Nature 1979 280, N 5720:288–294.
[9] Kapitonov V. V., Jurka J. RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons PLoS Biol 2005 3, N 6:e181.
[10] Corcoran A. E., Riddell A., Krooshoop D., Venkitaraman A. R. Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor Nature 1998 391, N 6670 P. 904–907.
[11] Fuxa M., Skok J., Souabni A., Salvagiotto G., Roldan E., Busslinger M. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene Genes Develop 2004 18, N 4:411–422.
[12] Su I. H., Tarakhovsky A. Epigenetic control of B cell differentiation Semin. Immunol 2005 17, N 2:167–172.
[13] Smith E., Sigvardsson M. The roles of transcription factors in B lymphocyte commitment, development, and transformation J. Leukoc. Biol 2004 75, N 6:973–981.
[14] Corcoran A. E. Immunoglobulin locus silencing and allelic exclusion Semin. Immunol 2005 17, N 2:141–154.
[15] Grawunder U., Leu T. M., Schatz D. G., Werner A., Rolink A. G., Melchers F., Winkler T. H. Down-regulation of RAG1 and RAG2 gene expression in preB cells after functional immunoglobulin heavy chain rearrangement Immunity 1995 3, N 5:601–608.
[16] Roldan E., Fuxa M., Chong W., Martinez D., Novatchkova M., Busslinger M., Skok J. A. Locus «decontraction» and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene Nat. Immunol 2004 6, N 2:31–41.
[17] Bolland D. J., Wood A. L., Afshar R., Featherstone K., Oltz E. M., Corcoran A. E. Antisense intergenic transcription precedes Igh D-to-J recombination and is controlled by the intronic enhancer Emju Mol. Cell. Biol 2007 27, N 15 P. 5523–5533.
[18] Sabbattini P., Dillon N. The 5-VpreB1 locus – a model system for studying gene regulation during early B cell development Semin. Immunol 2005 17, N 2:121– 127.
[19] Hu H., Wang B., Borde M., Nardone J., Maika S., Allred L., Tucker P. W., Rao A. Foxp1 is an essential transcriptional regulator of B cell development Nat. Immunol 2006 7, N 8:819–826.
[20] Lee Y., Ahn C., Han J., Choi H., Kim J., Yim J., Lee J., Provost P., Radmark O., Kim S., Kim V. N. The nuclear RNase III Drosha initiates microRNA processing Nature 2003 425, N 6956:415–419.
[21] He L., Hannon G. J. MicroRNAs: small RNAs with a big role in gene regulation Nat. Rev. Genet 2004 5, N 7:522– 531.
[22] Hutvagner G., Zamore P. D. RNAi: nature abhors a doublestrand Curr. Opin. Genet. Develop 2002 12, N 2 P. 225–232.
[23] Grimson A., Farh K. K.-H., Johnston W. K., Garrett-Engele P., Lim L. P., Bartel D. P. MicroRNA targeting specificity in mammals: determinants beyond seed pairing Mol. Cell 2007 27, N 1:91–105.
[24] Zhou B., Wang S., Mayr C., Bartel D. P., Lodish H. F. miR150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely Proc. Nat. Acad. Sci. USA 2007 104, N 17:7080– 7085.
[25] Papavasiliou F. N., Schatz D. G. Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity Cell 2002 109, Suppl:S35–S44.
[26] Shaffer A. L., Lin K. I., Kuo T. C., Yu X., Hurt E. M., Rosenwald A., Giltnane J. M., Yang L., Zhao H., Calame K., Staudt L. M. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program Immunity 2002 17, N 1:51–62.
[27] Delpy L., Le Bert M., Cogne M., Khamlichi A. A. Germ-line transcription occurs on both the functional and the nonfunctional alleles of immunoglobulin constant heavy chain genes Eur. J. Immunol 2003 33, N 8:2108–2113.
[28] Barreto V., Cumano A. Frequency and characterization of phenotypic Ig heavy chain allelically included IgM-expressing B cells in mice J. Immunol 2000 164, N 2:893–899.
[29] Lin S.-L., Miller J. D., Ying S.-Y. Intronic microRNA (miRNA) J. Biomed. Biotechnol 2006 2006, N 4:1–13.
[30] Halytskiy V. A. Mechanism of the initiation of DNA methylation de novo by small RNA. Eur. J. Cancer Suppl 2007 5, Suppl., N 4:75.
[31] Halytskiy V. A. Hypothesis of initiation of DNA methylation de novo and allelic exclusion by small RNAs Cell Tissue Biol 2008 2, N 2:97–106.
[32] Ohrt T., Mutze J., Staroske W., Weinmann L., Hock J., Crell K., Meister G., Schwille P. Fluorescence correlation spectroscopy and fluorescence cross-correlation spectroscopy reveal the cytoplasmic origination of loaded nuclear RISC in vivo in human cells Nucl. Acids Res 2008 36, N 20:6439–6449.
[33] Kim D. H., Saetrom P., Snive O. J., Rossi J. J. MicroRNAdirected transcriptional gene silencing in mammalian cells Proc. Nat. Acad. Sci. USA 2008 105, N 42:16230–16235.
[34] Piriyapongsa J., Jordan I. K. A family of human microRNA genes from miniature inverted-repeat transposable elements PLoS One 2007 2, N 2:e203.
[35] Hsieh C. L., Lieber M. R. CpG methylated minichromosomes become inaccessible for V(D)J recombination after undergoing replication. EMBO J. 1992; 11(1):315– 325.