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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Torkamani, Ali Feeney, Ann J. Schork, Nicholas J. Verma-gaur, Jiyoti Schaffer, Lana Head, Steven R. |
| Description | Author Affiliation: Verma-Gaur J ( Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.); |
| Abstract | Noncoding sense and antisense germ-line transcription within the Ig heavy chain locus precedes V(D)J recombination and has been proposed to be associated with Igh locus accessibility, although its precise role remains elusive. However, no global analysis of germ-line transcription throughout the Igh locus has been done. Therefore, we performed directional RNA-seq, demonstrating the locations and extent of both sense and antisense transcription throughout the Igh locus. Surprisingly, the majority of antisense transcripts are localized around two Pax5-activated intergenic repeat (PAIR) elements in the distal IghV region. Importantly, long-distance loops measured by chromosome conformation capture (3C) are observed between these two active PAIR promoters and Eµ, the start site of Iµ germ-line transcription, in a lineage- and stage-specific manner, even though this antisense transcription is Eµ-independent. YY1(-/-) pro-B cells are greatly impaired in distal V(H) gene rearrangement and Igh locus compaction, and we demonstrate that YY1 deficiency greatly reduces antisense transcription and PAIR-Eµ interactions. ChIP-seq shows high level YY1 binding only at Eµ, but low levels near some antisense promoters. PAIR-Eµ interactions are not disrupted by DRB, which blocks transcription elongation without disrupting transcription factories once they are established, but the looping is reduced after heat-shock treatment, which disrupts transcription factories. We propose that transcription-mediated interactions, most likely at transcription factories, initially compact the Igh locus, bringing distal V(H) genes close to the DJ(H) rearrangement which is adjacent to Eµ. Therefore, we hypothesize that one key role of noncoding germ-line transcription is to facilitate locus compaction, allowing distal V(H) genes to undergo efficient rearrangement. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 42 |
| Volume Number | 109 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2012-10-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Gene Rearrangement, B-Lymphocyte, Heavy Chain Physiology Immunoglobulin Heavy Chains Genetics Precursor Cells, B-Lymphoid Metabolism Protein Conformation RNA, Antisense RNA, Untranslated Transcription, Genetic Chromatin Immunoprecipitation Gene Knockdown Techniques Reverse Transcriptase Polymerase Chain Reaction Sequence Analysis, DNA YY1 Transcription Factor Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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