Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis

Yuan, Huairui; Ni, Li; Fu, Da; Ren, Jiale; Hui, Jingyi; Peng, Junjie; Liu, Yongfeng; Qiu, Tong; Jiang, Min; Pan, Qiang; Han, Ying; Wang, Xiaoming; Li, Qintong; Qin, Jun

doi:10.1172/jci94292

Cited by 138 publications

(130 citation statements)

References 68 publications

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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 CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which .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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Section: Discussionmentioning

confidence: 99%

A conserved genetic interaction between Spt6 and Set2 regulates H3K36 methylation

Gopalakrishnan

Winston

2018

Preprint

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“…Furthermore, the interplay of an epigenetic hallmark, such as DNA methylation, as negatively correlated with the H3K4me3 mark may explain the hypermethylation in the hypermutated samples . Meanwhile, frequent depletion of the H3K36 methyltransferase SETD2 (21%) and H3K4 methyltransferase SETD1B (34%) in CRC and H3K4 methyltransferase SETD1A (21%) in STAD, which are all associated with gene transcription, elongation, or alternative splicing, may also play a role in remodeling consistent hypermutated expression and DNA methylation patterns.…”

Section: Discussionmentioning

confidence: 99%

Deciphering molecular properties of hypermutated gastrointestinal cancer

Yang

et al. 2018

J Cellular Molecular Medi

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Great mutational heterogeneity is observed both across cancer types (>1000‐fold) and within a given cancer type, with a fraction harboring >10 mutations per million bases, thus termed hypermutation. We determined the genome‐wide effects of high mutation load on the transcriptome and methylome of two cancer types; namely, colorectal cancer (CRC) and stomach adenocarcinoma (STAD). Briefly, hierarchical clustering of the expression and methylation profiles showed that the majority of CRC and STAD hypermutated samples were mixed and separated from their respective non‐hypermutated samples, exceeding the boundary of tissue specificity. Further in‐detailed exploration uncovered that the underlying molecular mechanism may be related to the perturbation of chromatin remodeling genes.

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“…On other hand, a group proposed that loss of histone methyltransferase, SETD2, leads to upregulation of DVL-2 expression, thereby augmenting Wnt signaling to facilitate tumor malignancies. Their data demonstrated that SETD2 depletion enhanced mRNA expression and nuclear accumulation of DVL-2 which leads to hyper activation of Wnt signaling pathway resulting in colorectal cancer [161]. Therefore, the critical role of DVL in different cancer types makes it a suitable target for cancer therapy.…”

Section: Cancer Associationsmentioning

confidence: 99%

Dishevelled: A masterful conductor of complex Wnt signals

Sharma

Castro‐Piedras

Simmons

et al. 2018

Cellular Signalling

166

154

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The Dishevelled gene was first identified in Drosophila mutants with disoriented hair and bristle polarity [1-3]. The Dsh gene (Dsh/Dvl, in Drosophila and vertebrates respectively) gained popularity when it was discovered that it plays a key role in segment polarity during early embryonic development in Drosophila [4]. Subsequently, the vertebrate homolog of Dishevelled genes were identified in Xenopus (Xdsh), mice (Dvl1, Dvl2, Dvl3), and in humans (DVL1, DVL2, DVL3) [5-10]. Dishevelled functions as a principal component of Wnt signaling pathway and governs several cellular processes including cell proliferation, survival, migration, differentiation, polarity and stem cell renewal. This review will revisit seminal discoveries and also summarize recent advances in characterizing the role of Dishevelled in both normal and pathophysiological settings.

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Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis

Cited by 138 publications

References 68 publications

A conserved genetic interaction between Spt6 and Set2 regulates H3K36 methylation

A conserved genetic interaction between Spt6 and Set2 regulates H3K36 methylation

Deciphering molecular properties of hypermutated gastrointestinal cancer

Dishevelled: A masterful conductor of complex Wnt signals

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