Relieving Transcriptional Repression by Mutant Thyroid Hormone Receptor α in Resistance to Thyroid Hormone
Repression of gene expression by mutant thyroid hormone receptor alpha (TRα) causes tissue hypothyroidism in the human disorder of resistance to thyroid hormone. Romartinez-Alonso et al. (e00363-21) discovered that even highly deleterious, disease-associated, TRα mutants retain the ability to bind thyroid hormone and visualized this ligand within the crystal structure of a prototypic mutant receptor. This knowledge led them to design a thyroid hormone analogue which dissociates a transcription repression complex from mutant TRα better than endogenous ligand, providing proof of principle for developing such compounds for treatment of the disorder.
Reb1, Cbf1, and Pho4 Bias Histone Sliding and Deposition Away from Their Binding Sites
Nucleosome-depleted regions (NDRs), upstream transcription start sites, are vital for reliable expression of actively transcribing genes. NDRs are established by nucleosome-displacing factors (NDFs) through unknown mechanisms. Ghassabi Kondalaji and Bowman (e00472-21) demonstrate that NDFs regulate the direction of nucleosome sliding by chromatin remodelers and, in doing so, expand the length of the free DNA in the vicinity of NDF binding sites. Additionally, NDFs locally interfere with deposition of histone cores on DNA, favoring deposition away from their sites. Together, these data support a kinetic competition model between the histone core and NDFs that directly and indirectly influences nucleosome positioning.