Highlights d Serum starvation recruits TFIIIC at ADNP-bound Alu Elements (AEs) near Pol II genes d TFIIIC-associated histone acetylase activity acetylates H3K18 over the bound AEs d TFIIIC-bound acetylated AEs loop to contact CTCF at distal cell-cycle genes' promoters d CTCF-TFIIIC interaction ensures rapid cell-cycle genes' reactivation on serum exposure

The mammalian genome is shaped by the expansion of repetitive elements and its folding is governed by epigenetic modifications and architectural proteins. However, the precise way all these factors interact to coordinate genome structure and expression is poorly understood. Here we report that upon serum starvation TFIIIC, a general transcription factor, binds a subset of Alu elements close to cell cycle genes and rewires genome topology via direct histone acetylation and promoter-anchored chromatin loops to distant genes. These changes ensure basal transcription of crucial cell cycle genes and their re-activation upon serum re-exposure. Our study unveils a novel function of TFIIIC on gene expression and genome folding achieved through casting direct manipulation of the epigenetic state of Alu elements to adjust 3D genome function.

Retrotransposons are endogenous elements that have the ability to mobilise their DNA between different locations in the host genome. The Ty3 retrotransposon integrates with an exquisite specificity in a narrow window upstream of RNA Polymerase (Pol) III-transcribed genes, representing a paradigm for harmless targeted integration. Here we present the cryo-EM reconstruction at 4.0 Å of an active Ty3 strand transfer complex bound to TFIIIB transcription factor and a tRNA gene. The structure unravels the molecular mechanisms underlying Ty3 targeting specificity at Pol III-transcribed genes and sheds light into the architecture of retrotransposon machinery during integration. Ty3 intasome contacts a region of TBP, a subunit of TFIIIB, which is blocked by NC2 transcription regulator in RNA Pol II-transcribed genes. A newly-identified chromodomain on Ty3 integrase interacts with TFIIIB and the tRNA gene, defining with extreme precision the integration site position.

Transcription initiation is one of the key regulatory steps in expressing the genetic information encoded in the DNA. Mechanisms of RNA Pol II transcription have been extensively studied, whereas the structural basis of RNA Pol I and III transcription is still poorly defined. Three recent studies discussed here give a first glimpse into the molecular mechanisms underlying the process of RNA Pol I transcriptional initiation and reveal unexpected structural differences compared to the previously described homologous Pol II structures.

Retrotransposons are endogenous elements that have the ability to mobilise their DNA and integrate at different locations in the host genome. In budding yeast, the Ty3 retrotransposon integrates with an exquisite specificity in a narrow window upstream of RNA Polymerase III-transcribed genes, such as the genes of transfer RNAs, representing a paradigm for specific targeted integration. Here we present the cryo-EM reconstruction at 4.0 Å-resolution of an active Ty3 strand-transfer complex (Ty3 intasome) caught in the act of integrating onto a specific tRNA gene bound to the RNA Polymerase III general transcription factor TFIIIB, which is required for Ty3 specific targeting. The structure unravels the molecular mechanisms underlying Ty3 integration specificity at RNA Polymerase III-transcribed genes and sheds light into the architecture of a retrotransposon integration machinery during the process of strand transfer at a genomic locus. The Ty3 intasome establishes contacts with a region of the TATA-binding protein (TBP), a subunit of TFIIIB, which is blocked by the ubiquitous transcription regulator negative cofactor 2 (NC2) in RNA Pol II-transcribed genes. A previously unrecognised chromodomain of the Ty3 integrase mediates non-canonical interactions with TFIIIB and the tRNA gene itself, defining with extreme precision the position of the integration site. Surprisingly, Ty3 retrotransposon tethering to TFIIIB topologically resembles LEDGF/p75 transcription factor targeting by HIV retrovirus, highlighting mechanisms of convergent evolution by unrelated mobile elements and host organisms. The Ty3 intasome-TFIIIB-tRNA promoter complex presented here represents a detailed molecular snapshot of a general transcription factor's co-option by a mobile element, resulting in harmless integration into the host genome.