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Genetic screens reveal mechanisms for the transcriptional regulation of tissue-specific genes in normal cells and tumors.

ABSTRACT: The proper tissue-specific regulation of gene expression is essential for development and homeostasis in metazoans. However, the illegitimate expression of normally tissue-restricted genes-like testis- or placenta-specific genes-is frequently observed in tumors; this promotes transformation, but also allows immunotherapy. Two important questions are: how is the expression of these genes controlled in healthy cells? And how is this altered in cancer? To address these questions, we used an unbiased approach to test the ability of 350 distinct genetic or epigenetic perturbations to induce the illegitimate expression of over 40 tissue-restricted genes in primary human cells. We find that almost all of these genes are remarkably resistant to reactivation by a single alteration in signaling pathways or chromatin regulation. However, a few genes differ and are more readily activated; one is the placenta-expressed gene ADAM12, which promotes invasion. Using cellular systems, an animal model, and bioinformatics, we find that a non-canonical but druggable TGF-?/KAT2A/TAK1 axis controls ADAM12 induction in normal and cancer cells. More broadly, our data show that illegitimate gene expression in cancer is an heterogeneous phenomenon, with a few genes activatable by simple events, and most genes likely requiring a combination of events to become reactivated.

SUBMITTER: Naciri I

PROVIDER: S-EPMC6468300 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Genetic screens reveal mechanisms for the transcriptional regulation of tissue-specific genes in normal cells and tumors.

Naciri Ikrame I Laisné Marthe M Ferry Laure L Bourmaud Morgane M Gupta Nikhil N Di Carlo Selene S Huna Anda A Martin Nadine N Peduto Lucie L Bernard David D Kirsh Olivier O Defossez Pierre-Antoine PA

Nucleic acids research 20190401 7

The proper tissue-specific regulation of gene expression is essential for development and homeostasis in metazoans. However, the illegitimate expression of normally tissue-restricted genes-like testis- or placenta-specific genes-is frequently observed in tumors; this promotes transformation, but also allows immunotherapy. Two important questions are: how is the expression of these genes controlled in healthy cells? And how is this altered in cancer? To address these questions, we used an unbiase ...[more]

PMID: 30753595

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Project description:The lake sturgeon (Acipenser fulvescens) is an ancient, octoploid fish faced with conservation challenges across its range in North America, but a lack of genomic resources has hindered molecular research in the species. To support such research, we created a transcriptomic database from 13 tissues: brain, esophagus, gill, head kidney, heart, white muscle, liver, glandular stomach, muscular stomach, anterior intestine, pyloric cecum, spiral valve and rectum. The transcriptomes for each tissue were sequenced and assembled individually from a mean of 98.3 million (±38.9 million SD) reads each. In addition, an overall transcriptome was assembled and annotated with all data used for each tissue-specific transcriptome. All assembled transcriptomes and their annotations were made publicly available as a scientific resource. The non-gut transcriptomes provide important resources for many research avenues. However, we focused our analysis on messenger ribonucleic acid (mRNA) observations in the gut because the gut represents a compartmentalized organ system with compartmentalized functions, and seven of the sequenced tissues were from each of these portions. These gut-specific analyses were used to probe evidence of microbiome regulation by studying heterogeneity in microbial genes and genera identified from mRNA annotations. Gene set enrichment analyses were used to reveal the presence of photoperiod and circadian-related transcripts in the pyloric cecum, which may support periodicity in lake sturgeon digestion. Similar analyses were used to identify different types of innate immune regulation across the gut, while analyses of unique transcripts annotated to microbes revealed heterogeneous genera and genes among different gut tissues. The present results provide a scientific resource and information about the mechanisms of compartmentalized function across gut tissues in a phylogenetically ancient vertebrate. Database URL: https://figshare.com/projects/Lake_Sturgeon_Transcriptomes/133143.

Dataset Information

Genetic screens reveal mechanisms for the transcriptional regulation of tissue-specific genes in normal cells and tumors.

Publications

Genetic screens reveal mechanisms for the transcriptional regulation of tissue-specific genes in normal cells and tumors.

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