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The chromatin associated proteins HP1 behave as liver specific tumour suppressors in mice

ABSTRACT: Purpose : In this study we observed that inactivation of the genes encoding for the chromatin associated proteins HP1 lead to a highly increased predisposition of mice to develop tumours within liver. The purpose of this analysis was to identify and characterize genes whose expression was altered early on within livers of the HP1 mutant mice that could explain the tumorigenesis phenotype observed in very old animals. Results : this analysis revealed that only few genes (129 for HP1αKO, 84 for HP1αβliverKO and 87 for HP1αγliverKO) displayed differential expression between control and mutant animals [with a threshold of 1.5 fold difference and an adjusted pvalue≤0.05]. Besides several genes putatively involved in tumorigenesis, we found a significant enrichment in genes encoding several members of the family of transcriptional repressors KRAB-ZFP and presented data arguing that this increased expression resulted from their own loss of repressive activity because of the loss of interaction between their corepressor TRIM28 and HP1. Conclusions: our study represents the first demonstration that HP1 behave as tumour suppressors within liver and provide a comprehensive analysis of the underlying molecular mechanisms suggesting that HP1 main function within liver is to allow an appropriately regulated activity of the KRAB-ZFP/TRIM28/HP1 axis essential for liver homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE84734 | GEO | 2019/01/02

REPOSITORIES: GEO

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HP1 are dispensable for liver development and functions but are essential to prevent liver tumorigenesis

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The KRAB-ZFP/TRIM28 system exploits transposons to sharpen lineage-specific and activation-induced transcription in human adult T lymphocytes [ChIP-seq]

Project description:Transposable elements (TEs) are subjected to early embryonic repression through sequence-specific recruitment of KRAB zinc finger proteins (KRAB-ZFPs), their cofactor TRIM28 and associated chromatin modifiers. This prevents transposition and modulates TE-induced changes of gene expression in embryonic stem cells (ESCs). It leads to DNA methylation, a self-perpetuating modification considered as responsible for the permanent silencing of TEs after this period. Challenging this view, we reveal here that the KRAB/TRIM28 system keeps mediating a highly dynamic control of TEs and TE-mediated transcriptional influences in adult human cells. Using CD4+ T lymphocytes as an experimental model, we first observed that in these cells many TEs are still bound by TRIM28, the recruitment of which is dynamically regulated upon T cell receptor stimulation. Second, we determined that this transition reflects marked changes in the expression patterns of TE-binding KRAB-ZFPs. Finally, we could demonstrate that TRIM28 depletion induces broad transcriptional alterations in T cells, with de-repression notably of TE-based enhancers leading to the illegitimate activation of nearby genes and breaches of lineage-specific transcriptional restrictions. These data contribute to demonstrate that TEs and their KRAB-ZFP/TRIM28 control system are important regulators of gene expression in adult human cells.

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