Targeted protein degradation reveals a direct role of SPT6 in RNAPII elongation and termination

• Published in: Molecular cell Vol. 81; no. 15; pp. 3110 - 3127.e14
• Main Authors: Narain, Ashwin, Bhandare, Pranjali, Adhikari, Bikash, Backes, Simone, Eilers, Martin, Dölken, Lars, Schlosser, Andreas, Erhard, Florian, Baluapuri, Apoorva, Wolf, Elmar
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 05.08.2021; Cell Press
• Subjects: auxin; elongation; histone chaperone; mathematical modeling; RNA polymerase II; SPT6; SUPT6H; targeted protein degradation; termination; transcription; termination; auxin; transcription; mathematical modeling; SPT6; targeted protein degradation; elongation; SUPT6H; histone chaperone; RNA polymerase II
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.06.016

SPT6 is a histone chaperone that tightly binds RNA polymerase II (RNAPII) during transcription elongation. However, its primary role in transcription is uncertain. We used targeted protein degradation to rapidly deplete SPT6 in human cells and analyzed defects in RNAPII behavior by a multi-omics approach and mathematical modeling. Our data indicate that SPT6 is a crucial factor for RNAPII processivity and is therefore required for the productive transcription of protein-coding genes. Unexpectedly, SPT6 also has a vital role in RNAPII termination, as acute depletion induced readthrough transcription for thousands of genes. Long-term depletion of SPT6 induced cryptic intragenic transcription, as observed earlier in yeast. However, this phenotype was not observed upon acute SPT6 depletion and therefore can be attributed to accumulated epigenetic perturbations in the prolonged absence of SPT6. In conclusion, targeted degradation of SPT6 allowed the temporal discrimination of its function as an epigenetic safeguard and RNAPII elongation factor. [Display omitted] •Auxin-inducible degradation discriminates direct roles of human SPT6 in transcription•Acute loss of SPT6 globally impairs RNAPII processivity and speed•SPT6 is required for efficient transcription termination on protein-coding genes•Long-term loss of SPT6 ultimately results in cryptic intragenic transcription Histone chaperone SPT6 is essential for maintaining epigenetic integrity in the wake of transcription by RNAP II. By studying the effects of targeted acute depletion of SPT6 with multi-omics and mathematical modeling, Narain et al. uncovered direct roles of SPT6 in ensuring efficient transcription elongation and termination in human cells.