Winston, FredWarner, James Lawrence2025-09-1820252025-05-132025Warner, James Lawrence. 2025. The histone chaperone Spt6 controls chromatin structure through its conserved N-terminal domain. Doctoral Dissertation, Harvard University Graduate School of Arts and Sciences.32040893https://dash.harvard.edu/handle/1/42719746The disassembly and reassembly of nucleosomes by histone chaperones is an essential activity during eukaryotic transcription elongation. This highly conserved process maintains chromatin integrity by transiently removing nucleosomes as barriers and then restoring them in the wake of transcription. While transcription elongation requires multiple histone chaperones, there is little understanding of how most of them function and why so many are required. Here, we show that the histone chaperone Spt6 acts through its acidic, intrinsically disordered N-terminal domain (NTD) to bind histones and control chromatin structure. The Spt6 NTD is essential for viability and its histone binding activity is conserved between yeast and humans. The essential nature of the Spt6 NTD can be bypassed by changes in another histone chaperone, FACT, revealing a close functional connection between the two. Our results have led to a mechanistic model for dynamic cooperation between multiple histone chaperones during transcription elongation.application/pdfenchromatinhistone chaperonehistonesnucleosomeSpt6transcription elongationGeneticsBiologyMolecular biologyThesis or Dissertation2025-09-180000-0002-7960-7360