U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

SRX5730216: GSM3734922: CH12F3NCdel_sti_1; Mus musculus; OTHER
1 ILLUMINA (NextSeq 550) run: 31.2M spots, 4.7G bases, 1.7Gb downloads

Submitted by: NCBI (GEO)
Study: Chromatin Loop Extrusion Plays a Fundamental Mechanistic Role in Antibody Class Switching [GRO-Seq]
show Abstracthide Abstract
In a B lymphocyte immunoglobulin heavy chain locus (IgH), a developmentally assembled V(D)J exon encoding an antibody variable region lies upstream of exons encoding a m constant region (Cm), allowing generation of m?IgH chain transcripts and IgM-class antibodies1. Mouse IgH class switch recombination (CSR) replaces Cm?with one of 6 sets of constant region exons (CHs) that lie 100-200kb downstream1. Each CH is flanked upstream by a promoter, non-coding I-exon, and long repetitive switch (S) region1,2. Cytokines/activators induce specific I-promoter transcription and activation-induced cytidine deaminase (AID)2,3. AID is transcriptionally-targeted to initiate DNA breaks in Sm and activated downstream acceptor S regions, which are joined in deletional orientation to complete CSR4,5. 3'IgH regulatory region (3'IgHRR) enhancers control upstream I promoters and, thereby, CSR via linear competition involving I promoter/3'IgHRR interactions6-11. Here, we report that synapsis of regulatory elements, S regions and DSBs for CSR is achieved by chromatin loop extrusion. In naive B cells, 3'IgHRR enhancers and adjacent 3'IgH CTCF-binding elements (CBEs) interact via loop extrusion with the upstream Igh intronic enhancer (iEm)/Sm locale to generate dynamic 200kb 3'Igh basal loop. In CSR-activated B cells, induced transcription from I-promoters within this basal loop generates dynamic sub-loops that directionally align Sm and target S regions near the 3'IgHRR for CSR. In CH12F3 B lymphoma cells, inactivation of the constitutively active Ia-promoter abrogates looping and CSR to Sa, while activating transcription, looping, and CSR to upstream S regions. CBEs inserted upstream of Ia in convergent orientation with 3'IgH CBEs generate sub-loops that activate inversional Sa CSR. In I?-promoter-deleted CH12F3 cells, this ectopic CBE-based sub-loop inactivates upstream S region CSR, while transcriptionally activating non-S region sequences adjacent to the inserted CBEs for S? synapsis and CSR. Together, our findings implicate chromatin loop extrusion in the “unprecedented mechanism”5 by which Igh organization in cis promotes orientation-specific CSR DSB joining. Overall design: We performed CSR-HTGTS-Seq, 3C-HTGTS, GRO-Seq and ChIP-Seq in mature splenic B cells with different stimulation and different mutants of CH12F3 cells to study roles of cohesin-mediated chromatin loop extrusion in IgH class switch recombination.
Sample: CH12F3NCdel_sti_1
SAMN11491228 • SRS4667775 • All experiments • All runs
Organism: Mus musculus
Library:
Instrument: NextSeq 550
Strategy: OTHER
Source: TRANSCRIPTOMIC
Selection: other
Layout: PAIRED
Construction protocol: Briefly, 10 million cells were collected and permeabilized with the buffer (10 mM Tris-HCl pH 7.4, 300 mM sucrose, 10 mM KCl, 5 mM MgCl2, 1 mM EGTA, 0.05% Tween-20, 0.1% NP40 substitute, 0.5 mM DTT, protease inhibitors and Rnase inhibitor). The permeabilized cells were resuspended in 100 ml of storage buffer (10 mM Tris-HCl pH 8.0, 25% (V/V) glycerol, 5 mM MgCl2, 0.1 mM EDTA and 5 mM DTT) for nuclear run-on with 2X run-on mix (5 mM Tris-HCl PH 8.0, 2.5 mM MgCl2, 0.5 mM DTT, 150 mM KCl, 0.5 mM ATP, 0.5 mM CTP, 0.5 mM GTP, 0.5 mM BrUTP, RNase inhibitor, 1% sarkosyl) at 37o for 5 min. RNA was extracted by Trizol and followed by hybrolyzation with NaOH at a final concentration of 0.2 N on ice for 18 min. After quenching with ice-cold Tris-HCl PH6.8 at a final concentration of 0.55 M and exchanging buffer via Bio-Rad P30 columns, the RNA was incubated with Br-dU antibody-conjugated beads (Santa Cruz biotechnology, sc-32323-ac) for 1 hr. The enriched run-on samples were incubated with RppH (NEB, M0356S) and hydroxyl repair with T4 PNK (NEB, M0201S), followed by ligating the 5' and 3' RNA adaptor. RT-PCR was performed from the adaptor-ligated RNA to obtain cDNA Half of the cDNA was subjected to making Groseq libraries by two rounds of PCR with barcode primers. 200-500 bp products from the first round of PCR were subjected to the second round of PCR with the number of PCR cycles determined by test PCR amplification. The second round of PCR products were size-selected by SPRIselect beads (Beckman Coulter, B23318).
Experiment attributes:
GEO Accession: GSM3734922
Links:
Runs: 1 run, 31.2M spots, 4.7G bases, 1.7Gb
Run# of Spots# of BasesSizePublished
SRR895026831,236,3794.7G1.7Gb2019-09-26

ID:
7714063

Supplemental Content

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...