Modulation of gene expression dynamics by co-transcriptional histone methylations

Abstract

Co-transcriptional methylations of histone H3 at lysines 4 and 36, highly conserved methyl marks from yeast to humans, have profound roles in regulation of histone acetylation. These modifications function to recruit and/or activate distinct histone acetyltransferases (HATs) or histone deacetylases (HDACs). Whereas H3K4me3 increases acetylation at promoters via multiple HATs, H3K4me2 targets Set3 HDAC to deacetylate histones in 5' transcribed regions. In 3' regions of genes, H3K36me2/3 facilitates deacetylation by Rpd3S HDAC and slows elongation. Despite their important functions in deacetylation, no strong effects on global gene expression have been seen under optimized or laboratory growth conditions. Instead, H3K4me2-Set3 HDAC and Set2-Rpd3S pathways primarily delay the kinetics of messenger RNA (mRNA) and long noncoding RNA (lncRNA) induction upon environmental changes. A majority of mRNA genes regulated by these pathways have an overlapping lncRNA transcription either from an upstream or an antisense promoter. Surprisingly, the distance between mRNA and lncRNA promoters seems to specify the repressive effects of the two pathways. Given that co-transcriptional methylations and acetylation have been linked to many cancers, studying their functions in a dynamic condition or during cancer progression will be much more important and help identify novel genes associated with cancers.

Figure 1

Model for regulation of co-transcriptional methylations. (a) At an early stage of transcription, C-terminal domain (CTD) phosphorylation at serine 5 recruits messenger RNA (mRNA) capping machinery and early termination factors. This modification also contributes to recruitment of Set1-COMPASS that methylates histone H3 at lysine 4 in 5′ transcribed regions. During transcription elongation, CTD phosphorylation on serine 2 functions to recruit mRNA splicing machinery and termination factors. In addition, serine 2 phosphorylation of CTD and low levels of serine 5 phosphorylation also create a binding site for Set2 histone methyltransferase (HMT) that methylates H3K36 in 3′ transcribed regions. (b, c) Factors that influence H3K4 and H3K36 methylation patterns.

Figure 2

The downstream readers of co-transcriptional methylations. Multiple factors that positively and negatively affect gene expression bind co-transcriptional histone methylation of H3K4 and H3K36. (a) A distinct subunit (indicated by smaller circles) from multiple histone acetyltransferases (HATs) including NuA3, NuA4, SAGA and HBO1 HATs and TFIID complex binds H3K4me3. In addition, histone deacetylases (HDACs), Rpd3L in yeast and Sin3a-HDAC1 in mammals also interact with H3K4me3 via their specific subunits. (b) Factors that influence transcription bind to H3K4me2. The Set3 PHD finger and NRDc associated with HDACs preferentially bind H3K4me2. (c) Chromatin regulators that interact with H3K36me3. Two PHD finger subunits, Nto1 and Pdp3 of NuA3 HAT and Eaf3 chromodomain of both NuA4 HAT and Rpd3S HDAC interact with H3K36me3. The PWWP domain of Ioc4, a subunit of chromatin remodeler, ISW1 also binds H3K36me3.

Figure 3

Model for regulation of histone acetylation and gene induction by Set3 HDAC. (a) The C-terminal domain (CTD)-interacting Set1 HMT deposits H3K4me3 and H3K4me2 to promoters and 5′ transcribed regions, respectively. NuA3 and NuA4 HATs may acetylate histones at promoters via the interaction between PHD finger proteins, Yng1 and Yng2 and H3K4me3. In 5′ transcribed regions, the Set3 PHD finger binds H3K4me2 and two histone deacetylases (HDACs), Hos2 and Hst1 deacetylate histones. (b) Long noncoding RNA (lncRNA) transcription from an upstream or an antisense promoter targets H3K4me2 and Set3 HDAC to messenger RNA (mRNA) promoters. Deacetylation by Set3 HDAC delays gene induction upon environmental changes. Transcription from the mRNA promoter of a gene places H3K4me2 to 5′ transcribed regions and Set3 HDAC slows the kinetics of lncRNA induction.

Figure 4

Model for modulation of acetylation and gene induction by the Set2-Rpd3S pathway. (a) Set2 HMT interacts with elongating RNA polII and methylates on H3K36 in 3′ transcribed regions. Eaf3 chromodomain binds H3K36me2/3 and Rco1 PHD finger interacts with histone tails to stabilize chromatin binding of Rpd3S. Rpd3 deacetylates histones to slow elongation and suppress cryptic promoters. (b) lncRNA transcription from an upstream or an antisense promoter targets H3K36me3 and Rpd3S HDAC to mRNA promoters. Deacetylation at mRNA promoters by Rpd3S slows gene induction. Transcription from the mRNA promoter of a gene localizes H3K36me3 to inducible cryptic promoters. Deacetylation by Rpd3S histone deacetylase (HDAC) delays the rate of lncRNA induction. HMT, histone methyltransferase; lncRNA, long noncoding RNA; mRNA, messenger RNA; RNA polII, RNA polymerase II.

Figure 5

Model for regulation of gene induction by lncRNA transcription and two HDACs. Set3 HDAC and the Set2-Rpd3S pathway negatively regulate the kinetics of AAD10 and DCI1 induction, respectively. H3K4me2 and Set3 HDAC are targeted to DCI1 mRNA promoter via an overlapping lncRNA transcription and slow DCI1 induction. In contrast, lncRNA transcription from an upstream promoter of AAD10 targets H3K36me3 and Rpd3S to AAD10 mRNA promoter. Surprisingly, shortening the distance between the two promoters of AAD10 replaces H3K36me3-Rpd3S with H3K4me2-Set3 HDAC for AAD10 repression. Thus, position of the lncRNA promoter may be important for specifying the repressive effects of the two HDACs. HDAC, histone deacetylase; mRNA, messenger RNA; lncRNA, long noncoding RNA.