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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Richard Wolfe; Xinhao Liu
1.A sort of lymphocytes
2.Related to Cell mediated immunity
3.Have T Cell recepor(Tcr) on the surface
1.A sort of lymphocytes
2.Related to humoral immunity
3.Have Bcr on the surface
T cell receptor
Alpha and d chain
HMGB1 or HMGB2 bind Spacers
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?
Antigen receptor locus architecture and nuclear location work together with locus accessibility to ensure order, fidelity and allelic exclusion during the VDJ recombination
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.
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
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
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
CTCF and its cofactor, cohesin, have a fundamental role in regulating locus conformation and V(D)J rearrangement of the antigen receptor loci.
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