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2015 ; 194
(5
): 2380-9
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Constraints contributed by chromatin looping limit recombination targeting during
Ig class switch recombination
#MMPMID25624452
Feldman S
; Achour I
; Wuerffel R
; Kumar S
; Gerasimova T
; Sen R
; Kenter AL
J Immunol
2015[Mar]; 194
(5
): 2380-9
PMID25624452
show ga
Engagement of promoters with distal elements in long-range looping interactions
has been implicated in regulation of Ig class switch recombination (CSR). The
principles determining the spatial and regulatory relationships among Igh
transcriptional elements remain poorly defined. We examined the chromosome
conformation of C region (CH) loci that are targeted for CSR in a
cytokine-dependent fashion in mature B lymphocytes. Germline transcription (GLT)
of the ?1 and ? CH loci is controlled by two transcription factors,
IL-4-inducible STAT6 and LPS-activated NF-?B. We showed that although STAT6
deficiency triggered loss of GLT, deletion of NF-?B p50 abolished both GLT and ?1
locus:enhancer looping. Thus, chromatin looping between CH loci and Igh enhancers
is independent of GLT production and STAT6, whereas the establishment and
maintenance of these chromatin contacts requires NF-?B p50. Comparative analysis
of the endogenous ?1 locus and a knock-in heterologous promoter in mice
identified the promoter per se as the interactive looping element and showed that
transcription elongation is dispensable for promoter/enhancer interactions.
Interposition of the LPS-responsive heterologous promoter between the
LPS-inducible ?3 and ?2b loci altered GLT expression and essentially abolished
direct IgG2b switching while maintaining a sequential ???3??2b format. Our study
provides evidence that promoter/enhancer looping interactions can introduce
negative constraints on distal promoters and affect their ability to engage in
germline transcription and determine CSR targeting.