Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes
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Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes. / Nepal, Chirag; Andersen, Jesper B.
In: Nature Communications, Vol. 14, 2712, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes
AU - Nepal, Chirag
AU - Andersen, Jesper B
N1 - © 2023. The Author(s).
PY - 2023
Y1 - 2023
N2 - Transcriptional regulation is commonly governed by alternative promoters. However, the regulatory architecture in alternative and reference promoters, and how they differ, remains elusive. In 100 CAGE-seq libraries from hepatocellular carcinoma patients, here we annotate 4083 alternative promoters in 2926 multi-promoter genes, which are largely undetected in normal livers. These genes are enriched in oncogenic processes and predominantly show association with overall survival. Alternative promoters are narrow nucleosome depleted regions, CpG island depleted, and enriched for tissue-specific transcription factors. Globally tumors lose DNA methylation. We show hierarchical retention of intragenic DNA methylation with CG-poor regions rapidly losing methylation, while CG-rich regions retain it, a process mediated by differential SETD2, H3K36me3, DNMT3B, and TET1 binding. This mechanism is validated in SETD2 knockdown cells and SETD2-mutated patients. Selective DNA methylation loss in CG-poor regions makes the chromatin accessible for alternative transcription. We show alternative promoters can control tumor transcriptomes and their regulatory architecture.
AB - Transcriptional regulation is commonly governed by alternative promoters. However, the regulatory architecture in alternative and reference promoters, and how they differ, remains elusive. In 100 CAGE-seq libraries from hepatocellular carcinoma patients, here we annotate 4083 alternative promoters in 2926 multi-promoter genes, which are largely undetected in normal livers. These genes are enriched in oncogenic processes and predominantly show association with overall survival. Alternative promoters are narrow nucleosome depleted regions, CpG island depleted, and enriched for tissue-specific transcription factors. Globally tumors lose DNA methylation. We show hierarchical retention of intragenic DNA methylation with CG-poor regions rapidly losing methylation, while CG-rich regions retain it, a process mediated by differential SETD2, H3K36me3, DNMT3B, and TET1 binding. This mechanism is validated in SETD2 knockdown cells and SETD2-mutated patients. Selective DNA methylation loss in CG-poor regions makes the chromatin accessible for alternative transcription. We show alternative promoters can control tumor transcriptomes and their regulatory architecture.
KW - Humans
KW - Transcriptome/genetics
KW - Chromatin
KW - Nucleosomes/genetics
KW - CpG Islands/genetics
KW - DNA Methylation/genetics
KW - Epigenesis, Genetic
KW - Liver Neoplasms/genetics
KW - Mixed Function Oxygenases/metabolism
KW - Proto-Oncogene Proteins/metabolism
U2 - 10.1038/s41467-023-38272-4
DO - 10.1038/s41467-023-38272-4
M3 - Journal article
C2 - 37169774
VL - 14
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 2712
ER -
ID: 346489378