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V(D)J Recombination and the Role of CTCF. Richard Wolfe; Xinhao Liu. T cell. 1.A sort of lymphocytes 2.Related to Cell mediated immunity 3.Have T Cell recepor(Tcr) on the surface. T cell. B cell. 1.A sort of lymphocytes 2.Related to humoral immunity 3.Have Bcr on the surface

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V d j recombination and the role of ctcf
V(D)J Recombination and the Role of CTCF

Richard Wolfe; Xinhao Liu


T cell

1.A sort of lymphocytes

2.Related to Cell mediated immunity

3.Have T Cell recepor(Tcr) on the surface

T cell


B cell

1.A sort of lymphocytes

2.Related to humoral immunity

3.Have Bcr on the surface

4.Make antiboty

B cell


Light chain

Heavy chain


What is vdj recombination
What is VDJ Recombination?

  • V(D)J recombination is Somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of immunoglobulins and T cell receptors.


The structure of antigen receptor genes

Immunoglobulin

Heavy chain

Light chain

T cell receptor

Beta-chain

Alpha and d chain


Initiation of recombination
Initiation of Recombination

  • RAG(RAG recombinase) is a protein complex encoded by genes RAG1 and RAG2

HMGB1 or HMGB2 bind Spacers


Order during VDJ recombination

1. lgh and Tcrb are assembled with D to J recombination preceding V to DJ recombination

2. Immunoglobulin light chain(lgk or lgl) or Tcra is initiated.

Allelic exclusion: lg loci recombine full only in B cell lineage and TRC loci recombine only in T cells.

Question: How are the order, fidelity and allelic exclusion regulated during VDJ recombination?


Answer

Antigen receptor locus architecture and nuclear location work together with locus accessibility to ensure order, fidelity and allelic exclusion during the VDJ recombination


Character of Accessibility

V(D)J recombination correlates with numerous markers of open chromatin,

germline transcription, activating histone modifications, nuclease accessibility and DNA hypomethylation, which indicate a tight connection between chromatin structure and targeting of recombination.

  • Character of Inaccessibility

  • A high nucleosome density, which affects direct positioning of RSSs on nucleosomes, cause steric constraints by nucleosome packing.

  • Deletion of enhancer accompanied by a loss of germline transcription

  • Deletion of promoter which has a more local effect.

  • antisense transcription


There are many other regulation of vdj recomnination
There are many other regulation of VDJ recomnination.

  • CTCF, H3K9, H3K4, transcription factor, chromatin remodeling complex


Ctcf as repressor or activator
CTCF as Repressor or Activator

CTCF – CCCTC Binding Factor

Connects and separates different chromatin domains through loop formation

Mouse embryonic stem cells

Four Types of Domains:

Formation of active domain

Formation of repressive domain

Formation of enhancer-promoter

Formation of domain barrier between active and inactive chromatin regions


Ctcf and the architecture of the igh locus
CTCF and the architecture of the Igh locus

Igh locus – V(D)J recombination

Heavy chain locus

Cohesin is a CTCF cofactor

Pre-proB stage is D-J recombination

ProB stage V-DJ recombination

CTCF and Cohesin binding sites

Cohesin binding at CTCF-sites more specific pattern in proB stage

b. PAIR – Pax5-activated intergenic repeat elements

PAIR elements bind with CTCF and mediate changes in locus conformation essential for V-DJ recombination

c. Pre-proB stage, CTCF bound to CB1/2 acts as an insulator, which stops antisense transcription and active chromatin from D spreading to V, thus limiting D-J recombination. In proB stage the barrier is released allowing V-DJ recombination

d. Model of CTCF mediated loops at preB stage assisting D-J recombination and at proB assisting V-DJ recombination


Ctcf cohesin and the igk and tcra loci
CTCF/Cohesin and the Igk and Tcra loci

Igk locus – VJ recombination

Light chain locus

Tcra loci – T cell

a. CTCF binding more specific in preB cells

Enlarged area shows CTCF site in Sis silencer as in igh locus

b. Approx. 60 CTCF binding sites of High and Low occupancy in V region

Model shows CTCF loop separating enhancers from the V region

c. Again, CTCF binding site at TEA act to insulate the C-Jx region from the Dad1 area and Tcrd area


Conclusion
Conclusion

CTCF and its cofactor, cohesin, have a fundamental role in regulating locus conformation and V(D)J rearrangement of the antigen receptor loci.


References
References

Images:

Chaumeil J, Skok J: The role of CTCF in regulating V(D)J recombination.Current Opinion in Immunology 2012, 24:153-159.

Image of T cell, B cell and anti body are from google.

Image of recombination process are from David G. Schatz* and Yanhong Ji, Recombination centres and the orchestration of V(D)J recombination. NATURE REVIEWS | IMMUNOLOGY 2011,11:251-263


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