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Histone H3K4 methylation is connected to gene transcription from yeast to humans, but its mechanistic role in transcription and chromatin dynamics remains poorly understood. Here, we investigated the functions for Set1 and Jhd2, the sole H3K4 methyltransferase and H3K4 demethylase, respectively, in S. cerevisiae. Our data show that Set1 and Jhd2 predominantly co-regulate transcription. To further understand the role for H3K4 methylation, we overexpressed Flag epitope-tagged SET1-G990E (a dominant hyperactive allele of SET1) in yeast using the constitutive ADH1 promoter (ADH1p). As a control, we also overexpressed Flag epitope-tagged wild type SET1 in yeast. Analysis of gene expression in set1-null, jhd2-null and wild type SET1 or hypeactive SET1-G990E overexpressing mutants together revealed that the transcriptional regulation at a sub-set of genes, inclduing those governing glycogen metabolism and ribosome biogenesis, is highly sensitive to any change (i.e., loss or gain) in H3K4 methylation levels. Overall, we find combined activities of Set1 and Jhd2 via dynamic modulation of H3K4 methylation contribute to positive or negative transcriptional regulation at shared target genes. Gene expression changes were generated from five different yeast strains representing wild type control, set1 null and jhd2 null mutants, and wild type SET1 or dominant hyperacive SET1-G990E overexpressing mutants. Three independent biological samples were grown for each strain, total RNA was isolated, libraries were prepared, sequenced, and analyzed separately.

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