Infoscience

Thesis

Transposable elements and their KRAB/KAP1 controllers broadly regulate transcription in adult human cells

KAP1 is a universal corepressor for the large family of KRAB-ZFP proteins that coordinates epigenetic silencing of endogenous retroelements (EREs) during early embryonic development. This process is essential not just to prevent replication of EREs, but also to control their regulatory influence on host genes. Although in differentiated cells the control of EREs is believed to be mainly DNA methylation-dependent, emerging evidence suggests that KAP1-dependent, histone-based repression might remain a key regulator of ERE expression and its influence on cellular gene networks. Using a combination of transcriptional and histone modification profiling, we have investigated the impact of KAP1 epigenetic regulation on the transcriptional dynamics of human CD4+ T cells. We found that KAP1 binding on subsets of EREs is maintained in differentiated CD4+ T cells, where its locus-specific recruitment is dynamically modulated along with the T cell activation status. KAP1 depletion by RNA interference leads to a global decrease in repressive histone modifications that is accompanied by broad transcriptional alterations. Indeed, not only a large fraction of EREs become derepressed, but their deregulation correlates with illegittimate activation of nearby genes. Correspondingly, loss of KAP1 unleashes the intrinsic regulatory activities that some EREs are endowed with, suggesting a functional link between control of mobile genetic elements and protection of lineage-specific transcriptional networks. These findings establish the KRAB/KAP1 system as an important safeguard of CD4+ T cells transcriptional identity and suggest a critical role in maintaining epigenetic silencing of ERE-based regulatory sequences in adult tissues. Furthermore, our study shed light onto a previously unappreciated contribution of retrotransposon-derived sequences to the complexity of the human T cell transcriptome. A better knowledge of the physiological transcriptional activity of these mobile genetic elements, as well as their control mechanisms throughout development, would greatly help the debate on their pathologic implications.

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