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| Status |
Public on Jul 08, 2024 |
| Title |
Mechanism for controlled assembly of transcriptional condensates by Aire [5'-ethynyl uridine RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
Transcriptional condensates play a crucial role in gene expression and regulation, yet their assembly mechanisms remain poorly understood. We here report a multi-layered mechanism for condensate assembly by Autoimmune regulator (Aire), an essential transcriptional regulator (TR) that orchestrates gene expression reprogramming for central T-cell tolerance. Aire condensates assemble on enhancers, stimulating local transcriptional activities and connecting disparate inter-chromosomal loci. This functional condensate formation hinges upon the coordination between three Aire domains: polymerization domain CARD, histone binding domain PHD1 and C-terminal tail (CTT). Specifically, CTT binds coactivators CBP/p300, recruiting Aire to CBP/p300-rich enhancers and promoting CARD-mediated condensate assembly. Conversely, PHD1 binds to the ubiquitous histone mark H3K4me0, keeping Aire dispersed throughout the genome until Aire nucleates on enhancers. Our findings showed that the balance between PHD1-mediated suppression and CTT-mediated stimulation of Aire polymerization is crucial to form transcriptionally active condensates at target sites, providing new insights into controlled polymerization of TRs.
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| Overall design |
AIRE is known to be dynamically expressed in a small subset of mTECs, which has made mechanistic studies using mTECs challenging. We thus utilized the human thymic epithelial cell line 4D6, in which AIRE expression was temporally controlled through a doxycycline (Dox)-inducible promoter, to investigate the mechanism of AIRE polymerization in the nucleus. We examined whether ectopic expression of AIRE in 4D6 cells could recapitulate AIRE behaviours in mTECs including broad transcriptomic changes post AIRE expression.
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| Contributor(s) |
Hur S, Huoh Y, Zhang Q |
| Citation(s) |
39169234 |
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| Submission date |
May 15, 2024 |
| Last update date |
Sep 30, 2024 |
| Contact name |
Qianxia Zhang |
| E-mail(s) |
qianxia.zhang@childrens.harvard.edu
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| Phone |
9018345955
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| Organization name |
Boston Children's Hospital
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| Street address |
3 Blackfan Circle, RM 3117.16
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (8)
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| GSM8268226 |
WT AIRE 4D6, no Dox, A-485, rep2 |
| GSM8268227 |
WT AIRE 4D6, 24hr Dox, DMSO, rep1 |
| GSM8268228 |
WT AIRE 4D6, 24hr Dox, DMSO, rep2 |
| GSM8268229 |
WT AIRE 4D6, 24hr Dox, A-485, rep1 |
| GSM8268230 |
WT AIRE 4D6, 24hr Dox, A-485, rep2 |
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| This SubSeries is part of SuperSeries: |
| GSE243825 |
Mechanism for controlled assembly of transcriptional condensates by Aire |
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| Relations |
| BioProject |
PRJNA1111781 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE267527_EUseq24hr_log2FCA485vsDMSO.bw |
209.9 Mb |
(ftp)(http) |
BW |
| GSE267527_EUseq24hr_log2FCdox.bw |
195.9 Mb |
(ftp)(http) |
BW |
| GSE267527_RAW.tar |
809.1 Mb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
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