Set1/COMPASS repels heterochromatin invasion at euchromatic sites by disrupting Suv39/Clr4 activity and nucleosome stability

Abstract

Protection of euchromatin from invasion by gene-repressive heterochromatin is critical for cellular health and viability. In addition to constitutive loci such as pericentromeres and subtelomeres, heterochromatin can be found interspersed in gene-rich euchromatin, where it regulates gene expression pertinent to cell fate. While heterochromatin and euchromatin are globally poised for mutual antagonism, the mechanisms underlying precise spatial encoding of heterochromatin containment within euchromatic sites remain opaque. We investigated ectopic heterochromatin invasion by manipulating the fission yeast mating type locus boundary using a single-cell spreading reporter system. We found that heterochromatin repulsion is locally encoded by Set1/COMPASS on certain actively transcribed genes and that this protective role is most prominent at heterochromatin islands, small domains interspersed in euchromatin that regulate cell fate specifiers. Sensitivity to invasion by heterochromatin, surprisingly, is not dependent on Set1 altering overall gene expression levels. Rather, the gene-protective effect is strictly dependent on Set1's catalytic activity. H3K4 methylation, the Set1 product, antagonizes spreading in two ways: directly inhibiting catalysis by Suv39/Clr4 and locally disrupting nucleosome stability. Taken together, these results describe a mechanism for spatial encoding of euchromatic signals that repel heterochromatin invasion.

Caenorhabditis elegans SET1/COMPASS Maintains Germline Identity by Preventing Transcriptional Deregulation Across Generations

“…Rather, loss of H3K4me3 may indirectly affect chromatin structure, and hence transcription on the X. Consistent with such a model, inactivation of SET1/COMPASS subunits results in global changes in repressive H3K9 methylation in both yeast and worms (Robert et al, 2014;Lee et al, 2019;Greenstein et al, 2020) and alters chromatin organization [(Herbette et al, 2017) (see text footnote 1)].…”

Combinatorial Action of Temporally Segregated Transcription Factors

“…Elongating RNA pol II can recruit the Set1/COMPASS complex, which methylates histone H3 at position K4 ( Ng et al., 2003 ). This modification has been shown to promote acetylation of histones on multiple different residues ( Ginsburg et al., 2014 ; Noma and Grewal, 2002 ; Taverna et al., 2006 ) and inhibits methylation on H3K9 ( Greenstein et al., 2020 ). Together, this can result in the destabilization of nucleosomes and prevent spreading of repressive chromatin onto transcriptionally active genes, all of which would favor active transcription ( Greenstein et al., 2020 ).…”

“…This modification has been shown to promote acetylation of histones on multiple different residues ( Ginsburg et al., 2014 ; Noma and Grewal, 2002 ; Taverna et al., 2006 ) and inhibits methylation on H3K9 ( Greenstein et al., 2020 ). Together, this can result in the destabilization of nucleosomes and prevent spreading of repressive chromatin onto transcriptionally active genes, all of which would favor active transcription ( Greenstein et al., 2020 ). All components of the Set1/COMPASS complex were identified in a genetic screen as being necessary for robust lsy-6 expression and establishment of ASE asymmetry ( Poole et al., 2011 ).…”

The histone chaperone FACT facilitates heterochromatin spreading by regulating histone turnover and H3K9 methylation states

“…Cells containing HSS reporters were grown for flow cytometry experiments as described ( Greenstein et al, 2020 ). Flow cytometry was performed using a Fortessa X20 dual machine (Becton Dickinson) and high-throughput sampler (HTS) module.…”