Uncoupling the distinct functions of HP1 proteins during heterochromatin establishment and maintenance

• Published in: Cell reports (Cambridge) 2023-11, Vol.42 (11), p.113428-113428, Article 113428
• Main Authors: Seman, Melissa, Levashkevich, Alexander, Larkin, Ajay, Huang, Fengting, Ragunathan, Kaushik
• Format: Article
• Language: English
• Subjects: Cell Cycle Proteins - metabolism; chromatin compaction; Chromosomal Proteins, Non-Histone - metabolism; condensates; CP: Molecular biology; epigenetics; euchromatin; H3K9 methylation; heterochromatin; Heterochromatin - metabolism; histones; Histones - metabolism; inheritance; Schizosaccharomyces - genetics; Schizosaccharomyces - metabolism; Schizosaccharomyces pombe Proteins - genetics; Schizosaccharomyces pombe Proteins - metabolism; silencing; yeast
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113428

H3K9 methylation (H3K9me) marks transcriptionally silent genomic regions called heterochromatin. HP1 proteins are required to establish and maintain heterochromatin. HP1 proteins bind to H3K9me, recruit factors that promote heterochromatin formation, and oligomerize to form phase-separated condensates. We do not understand how these different HP1 properties are involved in establishing and maintaining transcriptional silencing. Here, we demonstrate that the S. pombe HP1 homolog, Swi6, can be completely bypassed to establish silencing at ectopic and endogenous loci when an H3K4 methyltransferase, Set1, and an H3K14 acetyltransferase, Mst2, are deleted. Deleting Set1 and Mst2 enhances Clr4 enzymatic activity, leading to higher H3K9me levels and spreading. In contrast, Swi6 and its capacity to oligomerize were indispensable during epigenetic maintenance. Our results demonstrate the role of HP1 proteins in regulating histone modification crosstalk during establishment and identify a genetically separable function in maintaining epigenetic memory. [Display omitted] •Swi6 is bypassed in heterochromatin establishment when Set1 and Mst2 are deleted•Deleting Set1 and Mst2 leads to high H3K9me levels and increased spreading•Swi6 cannot be bypassed for inheritance of H3K9me by deleting Set1 and Mst2•Swi6 oligomerization is distinctly required for epigenetic inheritance Seman et al. demonstrate how the major HP1 protein in fission yeast can be bypassed to establish epigenetic silencing but has essential, oligomerization-dependent functions during epigenetic inheritance. These findings challenge existing models that attribute HP1-dependent compaction or phase separation mechanisms to explain how heterochromatin silencing works.