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Histone modifiers play essential roles in controlling transcription and organizing eukaryotic genomes into functional domains. Here, we show that Set1, the catalytic subunit of the highly conserved Set1C/COMPASS complex responsible for histone H3K4 methylation (H3K4me), behaves as a repressor of the transcriptome largely independent of Set1C and H3K4me in the fission yeast Schizosaccharomyces pombe. Intriguingly, while Set1 is enriched at highly expressed and repressed loci, Set1 binding levels do not generally correlate with the levels of transcription. We show that Set1 is recruited by the ATF/CREB homolog Atf1 to heterochromatic loci and promoters of stress-response genes. Moreover, we demonstrate that Set1 coordinates with the class II histone deacetylase Clr3 in heterochromatin assembly at prominent chromosomal landmarks and repression of the transcriptome that includes Tf2 retrotransposons, noncoding RNAs, and regulators of development and stress-responses. Our study delineates a molecular framework for elucidating the functional links between transcriptome control and chromatin organization. DOI: http://dx.doi.org/10.7554/eLife.04506.001, eLife digest Genes can be turned on or off at different times in an organism's life. In humans, yeast and other eukaryotes, this is mainly controlled by the way DNA is packaged with proteins—known as histones—in a structure called chromatin. Genes that are switched on, or only temporarily switched off, are associated with areas of the genome where the chromatin is loosely packed. In contrast, genes that remain switched off for long periods of time are found in regions—known as heterochromatin—where the chromatin is tightly packed. There are many enzymes that can modify histones to change the structure of chromatin. One enzyme—called Set1—adds a methyl tag to chromatin, which is known to be associated with genes being switched on. However, Lorenz et al. found that Set1 also has other roles in modifying chromatin in the yeast Schizosaccharomyces pombe. The experiments found that Set1 helps to keep genes switched off and that this role is largely independent of its ability to add the methyl tag to chromatin. Set1 is recruited to many sites across the genome by another protein called Atf1, which is involved in the cell's response to environmental stresses. Lorenz et al. believe that this helps to put these genes in a ‘poised’ off state so that they are ready to be switched on rapidly if needed. Set1 also works with another protein that removes acetyl tags—which encourage chromatin to be less tightly packed—from histones. Together, both proteins contribute to the assembly of heterochromatin and keep genes involved in development and stress responses switched off when they are not required. Collectively, these experiments reveal unexpected and important insights into how Set1—which plays critical roles in many aspects of human health including aging and cancer—works in cells. DOI: http://dx.doi.org/10.7554/eLife.04506.002