Histone H3K36 methylation regulates pre-mRNA splicing in<i>Saccharomyces cerevisiae</i>

Sorenson, Matthew; Jha, Deepak Kumar; Ucles, Stefanie A.; Flood, Danielle M.; Strahl, Brian D.; Stevens, Scott W.; Kress, Tracy L.

doi:10.1080/15476286.2016.1144009

Cited by 50 publications

(43 citation statements)

References 82 publications

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“…Interestingly, mutants that lacked H3K36me3, but not H3K36me1 or H3K36me2, rescued the phenotype ( set2- Δ 31-39 and set2-R195C ). In contrast, the catalytically-dead SET2 mutant ( set2-H199L ) (Sorenson et al, 2016) and a construct with a truncation of the RNAPII interaction domain ( set2-1-618 ) (Kizer et al, 2005) failed to rescue the phenotype of set2 Δ cells. These results highlight an important role for H3K36me1/me2, but not H3K36me3, in mediating proper nutrient response.…”

Section: Resultsmentioning

confidence: 99%

H3K36 Methylation Regulates Nutrient Stress Response in Saccharomyces cerevisiae by Enforcing Transcriptional Fidelity

et al. 2017

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SUMMARY Set2-mediated histone methylation at H3K36 regulates diverse activities including DNA repair, mRNA splicing and suppression of inappropriate (cryptic) transcription. Although failure of Set2 to suppress cryptic transcription has been linked to decreased life span, the extent to which cryptic transcription influences other cellular functions is poorly understood. Here, we uncover a role for H3K36 methylation in the regulation of the nutrient stress response pathway. We found the transcriptional response to nutrient stress was dysregulated in SET2-deleted (set2Δ) cells and was correlated with genome-wide bi-directional cryptic transcription that originated from within gene bodies. Antisense transcripts arising from these cryptic events extended into the promoters of the genes from which they arose and were associated with decreased sense transcription under nutrient stress conditions. These results suggest that Set2-enforced transcriptional fidelity is critical to the proper regulation of inducible and highly regulated transcription programs.

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Section: Resultsmentioning

confidence: 99%

H3K36 Methylation Regulates Nutrient Stress Response in Saccharomyces cerevisiae by Enforcing Transcriptional Fidelity

et al. 2017

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“…Second, this regulation provides the opportunity to regulate H3K36me2/me3 in different conditions. For example, recent studies have provided evidence that H3K36 methylation is important for nutrient stress response 31,60 , carbon source shifts 61 , DNA damage responses 62-65 , splicing [66][67][68][69] , and aging 70,71 . Therefore, the Set2 autoinhibitory domain may serve as a target for additional regulators under particular growth conditions.…”

Section: Discussionmentioning

confidence: 99%

A conserved genetic interaction between Spt6 and Set2 regulates H3K36 methylation

Gopalakrishnan

Winston

2018

Preprint

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2The transcription elongation factor Spt6 and the H3K36 methyltransferase Set2 are both required for H3K36 methylation and transcriptional fidelity in Saccharomyces cerevisiae. By selecting for suppressors of a transcriptional defect in an spt6 mutant, we have isolated dominant SET2 mutations (SET2 sup mutations) in a region encoding a proposed autoinhibitory domain. The SET2 sup mutations suppress the H3K36 methylation defect in the spt6 mutant, as well as in other mutants that impair H3K36 methylation. ChIP-seq studies demonstrate that the H3K36 methylation defect in the spt6 mutant, as well as its suppression by a SET2 sup mutation, occur at a step following the recruitment of Set2 to chromatin. Other experiments show that a similar genetic relationship between Spt6 and Set2 exists in Schizosaccharomyces pombe.Taken together, our results suggest a conserved mechanism by which the Set2 autoinhibitory domain requires multiple interactions to ensure that H3K36 methylation occurs specifically on actively transcribed chromatin.. CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/364521 doi: bioRxiv preprint first posted online Jul. 8, 2018; 3 IntroductionThe histone chaperone Spt6 is a highly conserved transcription elongation factor required for many aspects of transcription and chromatin structure. Spt6 binds directly to Rpb1, the largest subunit of RNA polymerase II (RNAPII) [1][2][3][4][5][6] , to histones and nucleosomes [7][8][9] , and to the essential transcription factor Spn1/Iws1 9-12 . Mutations in S. cerevisiae SPT6 cause genome-wide changes in histone occupancy [13][14][15][16] and impair several histone modifications, including H3K36 di-and trimethylation (H3K36me2/me3) catalyzed by the H3K36 methyltransferase Set2 [17][18][19][20] . Mutations in SPT6 also cause greatly elevated levels of transcripts that arise from within coding regions on both sense and antisense strands, known as intragenic transcription 15,[21][22][23][24] . Intragenic transcription has recently emerged as a mechanism to express alternative genetic information within a coding region (for example, [25][26][27][28][29] ).Regulation of intragenic transcription by Spt6 occurs, at least in part, by its regulation of H3K36 methylation, as a deletion of SET2 also causes genome-wide expression of intragenic transcripts 17,30,31 . Set2 normally represses intragenic transcription via its association with RNAPII during transcription elongation, resulting in H3K36me2/me3 over gene bodies [32][33][34] . This histone modification is required for the co-transcriptional function of the Rpd3S histone deacetylase complex 17,[35][36][37][38] . Deacetylation by Rpd3S over transcribed regions is believed to maintain a repressive environment that prevents intragenic transcription. Regulation of intragenic transcription by H3K36 methylation is co...

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“…The histone mark H3K36me3 is known to regulate splicing (Ho et al, 2016;Kolasinska-zwierz et al, 2009;Sorenson et al, 2016). Previously it was reported that the genes, whose splicing is co-regulated by Med23 and hnRNP L, have high H3K36me3 levels (Huang et al, 2012).…”

Section: As Of Genes Co-regulated By Setd2 and Hnrnp L Have Distinct mentioning

confidence: 99%

The histone methyltransferase SETD2 couples transcription and splicing by engaging pre-mRNA processing factors through its SHI domain

Bhattacharya

Levy

Zhang

et al. 2020

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Heterogeneous ribonucleoproteins (hnRNPs) are RNA binding molecules that are involved in key processes such as RNA splicing and transcription. One such hnRNP protein, hnRNP L, regulates alternative splicing (AS) by binding to pre-mRNA transcripts. However, it is unclear what factors contribute to hnRNP L-regulated AS events. Using proteomic approaches, we identified several key factors that co-purify with hnRNP L. We demonstrate that one such factor, the histone methyltransferase SETD2, specifically interacts with hnRNP L in vitro and in vivo.This interaction occurs through a previously uncharacterized domain in SETD2, the SETD2-hnRNP L Interaction (SHI) domain, the deletion of which, leads to a reduced H3K36me3 deposition. Functionally, SETD2 regulates a subset of hnRNP L-targeted AS events. Our findings demonstrate that SETD2 by interacting with Pol II as well as hnRNP L, can mediate the crosstalk between the transcription and the splicing machinery.Alternative splicing (AS) of pre-mRNA is a crucial process that enables cells to synthesize different protein isoforms from the same gene (Kelemen et al., 2013). It occurs by the rearrangement of intron and exon elements that are joined by protein-RNA complexes known as the spliceosome to determine the mRNA coding sequence. It is estimated that 95% of the human genes undergo AS and this gives rise to the protein diversity needed for the varied cell types and functions from a limited set of genes (Pan et al., 2008)(Wang et al., 2008. AS functions in critical biological processes including cell growth, cell death, pluripotency, cell differentiation, development, and circadian rhythms (Barbosa-Morais et al., 2012)(Kalsotra and Cooper, 2011)(McGlincy et al., 2012.It is clear now that pre-mRNA splicing is coupled to transcription. Such coupling permits the sequential recognition of emerging splicing signals by the splicing factors (Oesterreich et al., 2011). Two models have been proposed to explain this coupling. The ''kinetic model'' proposes that changes in the rate of Pol II transcription influence the splice site selection process and hence, AS (Drahansky et al., 2016)(Schor et al., 2013. According to the ''recruitment model'', Pol II plays a central role in recruiting specific splicing regulators for co-transcriptional regulation of AS (Drahansky et al., 2016)(Schor et al., 2013).An example of specific splicing regulators that are important in pre-mRNA processing and could be players in the ''recruitment model'' are the RNA-binding heterogeneous nuclear ribonucleoproteins (hnRNPs). hnRNPs bind to splice sites in the pre-mRNA and regulate splicing (Lee et al., 2015). The role of hnRNPs in regulating gene expression is of increasing interest in disease research. The expression level of hnRNPs is altered in many types of cancer, suggesting their role in tumorigenesis (Han et al., 2013). In addition to cancer, many hnRNPs have also been linked to neurodegenerative diseases, such as spinal muscular atrophy, amyotrophic lateral sclerosis, Alzheimer's disease, and frontote...

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Histone H3K36 methylation regulates pre-mRNA splicing inSaccharomyces cerevisiae

Cited by 50 publications

References 82 publications

H3K36 Methylation Regulates Nutrient Stress Response in Saccharomyces cerevisiae by Enforcing Transcriptional Fidelity

H3K36 Methylation Regulates Nutrient Stress Response in Saccharomyces cerevisiae by Enforcing Transcriptional Fidelity

A conserved genetic interaction between Spt6 and Set2 regulates H3K36 methylation

The histone methyltransferase SETD2 couples transcription and splicing by engaging pre-mRNA processing factors through its SHI domain

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