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Series GSE125186 Query DataSets for GSE125186
Status Public on Jan 03, 2020
Title Impaired Cell Fate by Gain-of-function Mutations in a Chromatin Reader
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary We previously identified the YEATS domain-containing protein ENL as a reader of histone acetylation. Recently, hotspot mutations in ENL were frequently found in Wilms’ tumor, the most common type of pediatric kidney cancer. Here, we report that these cancer-associated mutations in the ENL YEATS domain confer gain of functions in transcriptional control and impair kidney differentiation by driving self-reinforced chromatin targeting. Ectopic expression of ENL mutants in kidney cell lines resulted in transcriptional changes of genes enriched in embryonic nephron progenitors and Wilms’ tumor. When tested in a nephrogenesis assay, ENL mutant expression led to undifferentiated structures resembling those observed in human Wilms’ tumor. Genome-wide analyses revealed that while mutant ENL bound to largely similar genomic loci as wild-type ENL, they exhibited increased occupancy at a subset of targets, including developmentally critical genes such as the HOXA cluster. The cancer-associated mutations enabled self-reinforced recruitment of ENL on chromatin by promoting self-association, resulting in the formation of discrete nuclear puncta that are characteristic of phase-separated biomolecular condensates. Enhanced occupancy of ENL mutants led to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci­­­­. Collectively, our studies represent, to our knowledge, the first discovery that cancer-associated mutations in a chromatin reader drive self-reinforced chromatin targeting, which in turns, perturbs developmental programs and derails normal cell fate control during mammalian development towards an oncogenic path.
Overall design Established stable cell lines to ectopic express either wild type or mutant human ENL in HEK293 and HK2 cell lines, and used these cell lines for Flag, CDK9 and Pol II S2P ChIP-seq and RNA-seq analysis.
Contributor(s) Cui X, Wen H, Wan L
Citation(s) 31853060
Submission date Jan 16, 2019
Last update date Jan 03, 2020
Contact name Hong Wen
Organization name Van Andel Research Institute
Department Center for Epigenetics
Street address 333 Bostwick Ave. N.E.
City Grand Rapids
State/province Michigan
ZIP/Postal code 49503
Country USA
Platforms (2)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (43)
GSM3564782 ChIPSeq.PolII_S2P_T1_mut
GSM3564783 ChIPSeq.PolII_S2P_T2_mut
GSM3564784 ChIPSeq.PolII_S2P_T3_mut
BioProject PRJNA515491
SRA SRP179759

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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE125186_RAW.tar 15.4 Gb (http)(custom) TAR (of BW, TXT)
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Raw data are available in SRA
Processed data provided as supplementary file

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