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Environ Microbiol 2021 Apr 31;23(4):2116-2131. Epub 2020 Dec 31.

School of Fundamental Sciences, Massey University, Palmerston North, New Zealand.

Recent studies have identified key genes that control the symbiotic interaction between Epichloë festucae and Lolium perenne. Here we report on the identification of specific E. festucae genes that control host infection. Read More

Genome Res 2020 11 5;30(11):1605-1617. Epub 2020 Oct 5.

Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

Histone H3 lysine 36 methylation (H3K36me) is a conserved histone modification associated with transcription and DNA repair. Although the effects of H3K36 methylation have been studied, the genome-wide dynamics of H3K36me deposition and removal are not known. We established rapid and reversible optogenetic control for Set2, the sole H3K36 methyltransferase in yeast, by fusing the enzyme with the light-activated nuclear shuttle (LANS) domain. Read More

Nucleic Acids Res 2020 10;48(18):10241-10258

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Spn1/Iws1 is a conserved protein involved in transcription and chromatin dynamics, yet its general in vivo requirement for these functions is unknown. Using a Spn1 depletion system in Saccharomyces cerevisiae, we demonstrate that Spn1 broadly influences several aspects of gene expression on a genome-wide scale. We show that Spn1 is globally required for normal mRNA levels and for normal splicing of ribosomal protein transcripts. Read More

PLoS One 2020 30;15(7):e0236876. Epub 2020 Jul 30.

Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.

PHRF1 (PHD and RING finger domain-containing protein 1) suppresses acute promyelocytic leukemia (APL) by promoting TGIF (TG-interacting factor) ubiquitination, while the PML-RARα protein interferes with PHRF1-mediated TGIF breakdown to facilitate APL. Beyond its role in APL tumorigenesis, PHRF1 contributes to non-homologous end-joining by linking H3K36 methylation and Nbs1 upon DNA damage insults. However, little is known regarding its function in tumor invasion. Read More

Cell Rep 2020 06;31(10):107751

Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Set2 co-transcriptionally methylates lysine 36 of histone H3 (H3K36), producing mono-, di-, and trimethylation (H3K36me1/2/3). These modifications recruit or repel chromatin effector proteins important for transcriptional fidelity, mRNA splicing, and DNA repair. However, it was not known whether the different methylation states of H3K36 have distinct biological functions. Read More

Nucleic Acids Res 2020 06;48(10):5407-5425

Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

Adjusting DNA structure via epigenetic modifications, and altering polyadenylation (pA) sites at which precursor mRNA is cleaved and polyadenylated, allows cells to quickly respond to environmental stress. Since polyadenylation occurs co-transcriptionally, and specific patterns of nucleosome positioning and chromatin modifications correlate with pA site usage, epigenetic factors potentially affect alternative polyadenylation (APA). We report that the histone H3K4 methyltransferase Set1, and the histone H3K36 methyltransferase Set2, control choice of pA site in Saccharomyces cerevisiae, a powerful model for studying evolutionarily conserved eukaryotic processes. Read More

Biotechnol Biofuels 2019 20;12:198. Epub 2019 Aug 20.

1National Glycoengineering Research Center, Shandong University, Qingdao, 266237 China.

Background: Enzymatic hydrolysis of lignocellulose by fungi is a key step in global carbon cycle and biomass utilization. Cellulolytic enzyme production is tightly controlled at a transcriptional level. Here, we investigated the roles of different histone lysine methylation modifications in regulating cellulolytic enzyme gene expression, as histone lysine methylation is an important process of chromatin regulation associated with gene transcription. Read More

Nat Commun 2019 08 22;10(1):3795. Epub 2019 Aug 22.

Department of Structural Biology, St. Jude Children's Research Hospital, 263 Danny Thomas Place, Memphis, TN, 38105, USA.

Histone H3 lysine 36 methylation (H3K36me) is a conserved histone modification deposited by the Set2 methyltransferases. Recent findings show that over-expression or mutation of Set2 enzymes promotes cancer progression, however, mechanisms of H3K36me are poorly understood. Set2 enzymes show spurious activity on histones and histone tails, and it is unknown how they obtain specificity to methylate H3K36 on the nucleosome. Read More

Cell Rep 2019 06;27(13):3760-3769.e4

Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

In the eukaryotic cell, spliceosomes assemble onto pre-mRNA cotranscriptionally. Spliceosome assembly takes place in the context of the chromatin environment, suggesting that the state of the chromatin may affect splicing. The molecular details and mechanisms through which chromatin affects splicing, however, are still unclear. Read More

Sci Rep 2019 02 26;9(1):2826. Epub 2019 Feb 26.

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Shugoshin family proteins are involved in various aspects of chromatin regulations, such as chromosome segregation, chromatin structure, and gene expression. In growing yeast and mammalian cells, C-terminal phosphorylation of histone H2A by Bub1 kinase is essential for the localization of Shugoshin proteins to chromatin. Here, we show that in stationary-phase cells, Bub1-mediated H2A phosphorylation is not necessary for chromatin localization of the Shugoshin paralog Sgo2 in Schizosaccharomyces pombe, or for Sgo2-dependent suppression of gene expression in subtelomeric regions. Read More

Nucleic Acids Res 2019 05;47(8):3888-3903

Department of Genetics, Harvard Medical School, Boston, MA, USA 02115.

The transcription elongation factor Spt6 and the H3K36 methyltransferase Set2 are both required for H3K36 methylation and transcriptional fidelity in Saccharomyces cerevisiae. However, the nature of the requirement for Spt6 has remained elusive. By selecting for suppressors of a transcriptional defect in an spt6 mutant, we have isolated several highly clustered, dominant SET2 mutations (SET2sup mutations) in a region encoding a proposed autoinhibitory domain. Read More

J Cell Sci 2019 03 25;132(6). Epub 2019 Mar 25.

CRUK-MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford, OX3 7DQ, UK

Replication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here, we show that cyclin-dependent kinase (CDK)-induced replication stress, resulting from Wee1 inactivation, is synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. Wee1 inactivation leads to increased dNTP demand and replication stress through CDK-induced firing of dormant replication origins. Read More

Elife 2018 11 23;7. Epub 2018 Nov 23.

Institute of Molecular Biology, University of Oregon, Eugene, United States.

Methylation of histone H3 at lysine 36 (H3K36me), a widely-distributed chromatin mark, largely results from association of the lysine methyltransferase (KMT) SET-2 with RNA polymerase II (RNAPII), but most eukaryotes also have additional H3K36me KMTs that act independently of RNAPII. These include the orthologs of ASH1, which are conserved in animals, plants, and fungi but whose function and control are poorly understood. We found that has just two H3K36 KMTs, ASH1 and SET-2, and were able to explore the function and distribution of each enzyme independently. Read More

Biophys Rep 2018 29;4(4):170-177. Epub 2018 Aug 29.

1National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101 China.

Histone H3K36 methylation is well-known for its role in active transcription. In , H3K36 methylation is mediated solely by SET2 during transcription elongation. In metazoans, multiple H3K36-specific methyltransferases exist and contribute to distinct biochemical activities and subsequent functions. Read More

G3 (Bethesda) 2018 11 6;8(11):3411-3420. Epub 2018 Nov 6.

Department of Molecular Genetics, University of Toronto, ON, M5S 1A8, Canada

Much of euchromatin regulation occurs through reversible methylation of histone H3 lysine-4 and lysine-36 (H3K4me and H3K36me). Using the budding yeast , we previously found that levels of H3K4me modulated temperature sensitive alleles of the transcriptional elongation complex Spt6-Spn1 through an unknown H3K4me effector pathway. Here we identify the Rpd3S histone deacetylase complex as the H3K4me effector underlying these Spt6-Spn1 genetic interactions. Read More

Nucleic Acids Res 2018 06;46(10):5061-5074

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

The Set2 methyltransferase and its target, histone H3 lysine 36 (H3K36), affect chromatin architecture during the transcription and repair of DNA double-stranded breaks. Set2 also confers resistance against the alkylating agent, methyl methanesulfonate (MMS), through an unknown mechanism. Here, we show that Schizosaccharomyces pombe (S. Read More

Development 2018 04 5;145(7). Epub 2018 Apr 5.

Max-Planck Institute of Biochemistry, Laboratory of Chromatin Biology, Am Klopferspitz 18, 82152 Martinsried, Germany

The Ash1 protein is a trithorax-group (trxG) regulator that antagonizes Polycomb repression at HOX genes. Ash1 di-methylates lysine 36 in histone H3 (H3K36me2) but how this activity is controlled and at which genes it functions is not well understood. We show that Ash1 protein purified from exists in a complex with MRG15 and Caf1 that we named AMC. Read More

Nucleic Acids Res 2018 02;46(3):1331-1344

Department of Biochemistry & Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.

Methylation of histone H3 lysine 36 (H3K36me) by yeast Set2 is critical for the maintenance of chromatin structure and transcriptional fidelity. However, we do not know the full range of Set2/H3K36me functions or the scope of mechanisms that regulate Set2-dependent H3K36 methylation. Here, we show that the APC/CCDC20 complex regulates Set2 protein abundance during the cell cycle. Read More

Front Genet 2017 15;8:175. Epub 2017 Nov 15.

Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, United States.

Traumatic brain injury (TBI) can cause persistent pathological alteration of neurons. This may lead to cognitive dysfunction, depression and increased susceptibility to life threatening diseases, such as epilepsy and Alzheimer's disease. To investigate the underlying genetic and molecular basis of TBI, we subjected to mild closed head trauma and found that mitochondrial activity is reduced in the brains of these flies 24 h after inflicting trauma. Read More

Genetics 2018 01 16;208(1):153-171. Epub 2017 Nov 16.

Institute of Plant Biology and Biotechnology, Westfälische Wilhelms-Universität Münster, 48143, Germany

In this work, we present a comprehensive analysis of the H3K36 histone methyltransferases Set2 and Ash1 in the filamentous ascomycete In , one single methyltransferase, Set2, confers all H3K36 methylation, while there are two members of the Set2 family in filamentous fungi, and even more H3K36 methyltransferases in higher eukaryotes. Whereas the yeast Set2 homolog has been analyzed in fungi previously, the second member of the Set2 family, designated Ash1, has not been described for any filamentous fungus. Western blot and ChIP-Seq analyses confirmed that Set2 and Ash1 are H3K36-specific histone methyltransferases that deposit H3K36me3 at specific loci: Set2 is most likely responsible for H3K36 methylation of euchromatic regions of the genome, while Ash1 methylates H3K36 at the subtelomeric regions (facultative heterochromatin) of all chromosomes, including the accessory chromosome XII. Read More

Elife 2017 09 14;6. Epub 2017 Sep 14.

The Francis Crick Institute, London, United Kingdom.

Cell differentiation programs require dynamic regulation of gene expression. During meiotic prophase in , expression of the kinetochore complex subunit Ndc80 is downregulated by a 5' extended long undecoded transcript isoform. Here we demonstrate a transcriptional interference mechanism that is responsible for inhibiting expression of the coding mRNA isoform. Read More

Cell Rep 2017 Sep;20(11):2693-2705

CRUK-MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK. Electronic address:

Chromatin modification through histone H3 lysine 36 methylation by the SETD2 tumor suppressor plays a key role in maintaining genome stability. Here, we describe a role for Set2-dependent H3K36 methylation in facilitating DNA replication and the transcriptional responses to both replication stress and DNA damage through promoting MluI cell-cycle box (MCB) binding factor (MBF)-complex-dependent transcription in fission yeast. Set2 loss leads to reduced MBF-dependent ribonucleotide reductase (RNR) expression, reduced deoxyribonucleoside triphosphate (dNTP) synthesis, altered replication origin firing, and a checkpoint-dependent S-phase delay. Read More

Fungal Genet Biol 2017 10 1;107:24-30. Epub 2017 Aug 1.

Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, Key Laboratory of Monitoring and Management of Crop Diseases and Pest Insects, Ministry of Education, Nanjing, China.

Histone H3 lysine 36 methylation (H3K36me) is generally associated with activation of gene expression in most eukaryotic cells. However, the function of H3K36me in filamentous fungi is largely unknown. Set2 is the sole lysine histone methyltransferase (KHMTase) enzyme responsible for the methylation of H3K36 in Saccharomyces cerevisiae. Read More

Elife 2017 07 18;6. Epub 2017 Jul 18.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, United States.

Recurrent somatic mutations of in aggressive pediatric high-grade gliomas generate K27M or G34R/V mutant histone H3.3. H3. Read More

Cell Rep 2017 06;19(11):2371-2382

Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

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 lifespan, 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. Read More

Oncol Rep 2017 Jun 4;37(6):3181-3188. Epub 2017 May 4.

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Spindle cell tumors are clinically heterogeneous but morphologically similar neoplasms. The term refers to the tumor cells' long and slender microscopic appearance. Distinct subgroups of spindle cell tumors are characterized by chromosomal translocations and also fusion genes. Read More

Mol Cell Biol 2017 07 29;37(14). Epub 2017 Jun 29.

Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, Scotland

Histone methylation at H3K4 and H3K36 is commonly associated with genes actively transcribed by RNA polymerase II (RNAPII) and is catalyzed by Set1 and Set2, respectively. Here we report that both methyltransferases can be UV cross-linked to RNA High-throughput sequencing of the bound RNAs revealed strong Set1 enrichment near the transcription start site, whereas Set2 was distributed along pre-mRNAs. A subset of transcripts showed notably high enrichment for Set1 or Set2 binding relative to RNAPII, suggesting functional posttranscriptional interactions. Read More

Cell Mol Life Sci 2017 09 6;74(18):3317-3334. Epub 2017 Apr 6.

Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC, 27599, USA.

Chromatin structure is a major barrier to gene transcription that must be disrupted and re-set during each round of transcription. Central to this process is the Set2/SETD2 methyltransferase that mediates co-transcriptional methylation to histone H3 at lysine 36 (H3K36me). Studies reveal that H3K36me not only prevents inappropriate transcriptional initiation from arising within gene bodies, but that it has other conserved functions that include the repair of damaged DNA and regulation of pre-mRNA splicing. Read More

BMB Rep 2017 Apr;50(4):162-163

Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 03760, Korea.

RNA polymerase II-interacting the Set2 methyltransferase co-transcriptionally methylates histone H3 at lysine 36 within the body of genes. This modification facilitates histone deacetylation by Rpd3S HDAC in 3' transcribed regions to suppress cryptic initiation and slow elongation. Although this pathway is important for global deacetylation, no strong effects have been seen on genome-wide transcription under optimized laboratory conditions. Read More

Nat Commun 2016 11 28;7:13534. Epub 2016 Nov 28.

Department of Life Science, Ewha Womans University, Seoul 03760, Korea.

H3K36 methylation by Set2 targets Rpd3S histone deacetylase to transcribed regions of mRNA genes, repressing internal cryptic promoters and slowing elongation. Here we explore the function of this pathway by analysing transcription in yeast undergoing a series of carbon source shifts. Approximately 80 mRNA genes show increased induction upon SET2 deletion. Read More