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| Status |
Public on Mar 30, 2022 |
| Title |
Targeting Xist with compounds that disrupt RNA structure and X-inactivation |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Although >98% of our genome is noncoding, nearly all drugs on the market target one of ~700 disease-related proteins. The historical reluctance to invest in noncoding RNA stems partly from requirements for drug targets to adopt a single stable conformation. Most RNAs can adopt several conformations of similar stabilities. RNA structures also remain challenging to determine. Nonetheless, an increasing number of diseases is now being attributed to noncoding RNA and the ability to target them would vastly expand the chemical space for drug development. Here we devise a screening strategy and identify small molecules that hit the non-coding RNA prototype, Xist. The X1 compound has drug-like properties and binds specifically to Xist’s RepA motif in vitro and in vivo. SAXS analysis reveals that RepA can adopt multiple conformations but favors one structure in solution. X1 binding reduces RepA’s conformational space, displaces cognate interacting protein factors (PRC2, SPEN), suppresses H3K27 trimethylation, and blocks initiation of X-inactivation. X1 inhibits cell differentiation and growth in a female-specific manner. Thus, RNA can be systematically targeted by drug-like compounds that disrupt RNA structure and epigenetic function.
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| Overall design |
Day 5 TST cells are subjected to drug or control and then used in three deep sequencing analyses, RNA sequencing, H3K27me3 ChIP, and Suz12 ChIP.
Please note that RAb5-*.div.RAb5-*bw files were generated from both input and ChIP samples, and are linked to the corresponding ChIP-Suz12* sample records.
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| Web link |
https://www.nature.com/articles/s41586-022-04537-z
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| Contributor(s) |
Aguilar R, Spencer KB, Kesner B, Rizvi NF, Badmalia MD, Mrozowich T, Mortison JD, Rivera C, Smith GF, Burchard J, Dandliker P, Patel TR, Nickbarg EB, Lee JT |
| Citation(s) |
35355011 |
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| Submission date |
Dec 09, 2019 |
| Last update date |
Apr 22, 2022 |
| Contact name |
barry A kesner |
| E-mail(s) |
kesner@molbio.mgh.harvard.edu
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| Phone |
6175197106
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| Organization name |
molecular biology
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| Street address |
49 charlemont street
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| City |
newton |
| State/province |
ma |
| ZIP/Postal code |
02461 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA594367 |
| SRA |
SRP235281 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE141683_DeSeq.RA4.cas.treated.rel.dmso.txt.gz |
8.1 Kb |
(ftp)(http) |
TXT |
| GSE141683_DeSeq.RA4.mus.treatd.rel.dmso.txt.gz |
564.6 Kb |
(ftp)(http) |
TXT |
| GSE141683_RA3_raw_counts.txt.gz |
1.6 Mb |
(ftp)(http) |
TXT |
| GSE141683_RA4.raw.counts.txt.gz |
684.5 Kb |
(ftp)(http) |
TXT |
| GSE141683_RA5_raw_counts.txt.gz |
1.6 Mb |
(ftp)(http) |
TXT |
| GSE141683_RAW.tar |
85.2 Gb |
(http)(custom) |
TAR (of BW) |
| GSE141683_RAb3-2.div.RAb3-1.cas.wig.bw |
540.9 Mb |
(ftp)(http) |
BW |
| GSE141683_RAb3-2.div.RAb3-1.comp.wig.bw |
543.1 Mb |
(ftp)(http) |
BW |
| GSE141683_RAb3-2.div.RAb3-1.mus.wig.bw |
540.7 Mb |
(ftp)(http) |
BW |
| GSE141683_RAb3-4.div.RAb3-3.cas.wig.bw |
541.2 Mb |
(ftp)(http) |
BW |
| GSE141683_RAb3-4.div.RAb3-3.comp.wig.bw |
541.4 Mb |
(ftp)(http) |
BW |
| GSE141683_RAb3-4.div.RAb3-3.mus.wig.bw |
540.4 Mb |
(ftp)(http) |
BW |
| GSE141683_RAb4.AnalyzeRepeats.fpkm_gt_1.genes_pm3000.chr13.comp.bed.gz |
3.5 Kb |
(ftp)(http) |
BED |
| GSE141683_RAb4.AnalyzeRepeats.fpkm_gt_1.genes_pm3000.chrX.comp.bed.gz |
4.1 Kb |
(ftp)(http) |
BED |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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