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

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. Overall design: H3K9me3 and KAP1 ChIP-seq in CD4+ T lymphocytes. Transcriptome profiling of control and KAP1 KD CD4+ T lymphocytes.