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Transcriptional and Epigenetic Mechanisms Regulating Normal and Aberrant Blood Cell Development pp 295–329Cite as

Epigenetic Control of T-Cell Receptor Locus Rearrangements in Normal and Aberrant Conditions

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Part of the book series: Epigenetics and Human Health ((EHH))

Abstract

V(D)J recombination is the process responsible for the exclusive expression of one antigen receptor form, either T-cell receptor (TCR) or immunoglobulin (Ig), per individual T or B lymphocyte, respectively. This process is, therefore, essential for adaptive immune responses in vertebrates and it consists of the assembly of disperse gene segments present at the TCR and Ig loci to obtain a genetic structure that is able to encode a functional protein. V(D)J recombination is highly regulated during lymphocyte development and depends on the activation of accessibility control elements (ACEs) to direct the recruitment of the specific endonuclease RAG-1/2 to its site-specific target sequences that flank the gene segments. The RAG-1/2-mediated DNA cleavage at these loci is controlled by changes in the epigenome. These changes are derived from chromatin modification, transcriptional elongation, the location of the loci within the nucleus, and the three-dimensional architecture of the loci, which is controlled by functional interplay among ACEs and their bound trans-factors. This epigenetic control ultimately leads to the juxtapositioning or synapsis of two gene segments that are normally distantly located and the recombination reaction itself. This process must be completed without any errors to avoid the potential risk of generating aberrant translocations that could result in the generation of leukemia. This chapter summarizes the advances in this area at the TCR loci and the importance of regulating this potentially risky process during thymocyte development.

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Abbreviations

ACE:

Accessibility control element

AgR:

Antigen receptor

AT:

Ataxia telangiectasia

ATM:

Ataxia telangiectasia mutated kinase

BCR:

B-cell receptor

bHLH:

Basic helix-loop-helix

C:

Constant

CTCF:

CCCTC-binding factor; constant region

CLP:

Common lymphoid progenitor

D:

Diversity

DN:

Double negative

DNA-PKcs:

DNA-dependent protein kinase

DP:

Double positive

Eα:

Tcra enhancer

Eβ:

Tcrb enhancer

Eδ:

Tcrd enhancer

Eγ:

Tcrg enhancer

FISH:

Fluorescence in situ hyhbridization

H3ac:

Histone H3 acetylation

H3K4me2/3:

Dimethylation or trimethylation of lysine 4 of histone H3

H3K9me2/3:

Dimethylation or trimethylation of lysine 9 of histone H3

H3K27me2/3:

Dimethylation or trimethylation of lysine 27 of histone H3

Ig:

Immunoglobulin

J:

Joining

LCR:

Locus control region

Lig4:

Cernunnos/XLF-Xrcc4/Dna ligase IV complex

N:

Non-template

NHEJ:

Nonhomologous end-joining

OS:

Omenn syndrome

RAG:

Recombination activating gene

RSS:

Recombination signal sequence

SCID:

Severe combined immunodeficiency disease

SP:

Single positive

T-ALL:

T-cell acute leukemia

TCR:

T-cell receptor

TEA:

T early α

TF:

Transcription factor

V:

Variable

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Acknowledgments

The authors are grateful for support from the Spanish goverment (BFU2009-08796), the Andalusian government (grants CTS-6587 and CVI-4526) and the European Regional Development Fund (ERDF/FEDER). We also thank Carlos Suñé for comments on the manuscript.

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  1. Department of Cellular Biology and Immunology, Instituto de Parasitología y Biomedicina “López-Neyra” (IPBLN-CSIC), Consejo Superior de Investigaciones Científicas, Avenida del Conocimiento s/n, 18016-Armilla, Granada, Spain

    Beatriz del Blanco, Úrsula Angulo & Cristina Hernández-Munain

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  1. Beatriz del Blanco
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  2. Úrsula Angulo
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  3. Cristina Hernández-Munain
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Correspondence to Cristina Hernández-Munain .

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  1. Institute of Biomedical Research, University of Birmingham Medical and Dental Sciences, Birmingham, United Kingdom

    Constanze Bonifer

  2. Institute of Biomedical Research, University of Birmingham Medical and Dental Sciences, Birmingham, United Kingdom

    Peter N. Cockerill

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del Blanco, B., Angulo, Ú., Hernández-Munain, C. (2014). Epigenetic Control of T-Cell Receptor Locus Rearrangements in Normal and Aberrant Conditions. In: Bonifer, C., Cockerill, P. (eds) Transcriptional and Epigenetic Mechanisms Regulating Normal and Aberrant Blood Cell Development. Epigenetics and Human Health. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-45198-0_12

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