EPIGENETICS https://doi.org/10.1080/15592294.2018.1503491 REVIEW Recognition of cancer mutations in histone H3K36 by epigenetic writers and readers Brianna J. Kleina, Krzysztof Krajewski b, Susana Restrepoa, Peter W. Lewis c, Brian D. Strahlb, and Tatiana G. Kutateladzea aDepartment of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA; bDepartment of Biochemistry & Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC, USA; cWisconsin Institute for Discovery, University of Wisconsin, Madison, WI, USA ABSTRACT ARTICLE HISTORY Histone posttranslational modifications control the organization and function of chromatin. In Received 30 May 2018 particular, methylation of lysine 36 in histone H3 (H3K36me) has been shown to mediate gene Revised 1 July 2018 transcription, DNA repair, cell cycle regulation, and pre-mRNA splicing. Notably, mutations at or Accepted 12 July 2018 near this residue have been causally linked to the development of several human cancers. These KEYWORDS observations have helped to illuminate the role of histones themselves in disease and to clarify Histone; H3K36M; cancer; the mechanisms by which they acquire oncogenic properties. This perspective focuses on recent PTM; methylation advances in discovery and characterization of histone H3 mutations that impact H3K36 methyla- tion. We also highlight findings that the common cancer-related substitution of H3K36 to methionine (H3K36M) disturbs functions of not only H3K36me-writing enzymes but also H3K36me-specific readers. The latter case suggests that the oncogenic effects could also be linked to the inability of readers to engage H3K36M. Introduction from yeast to humans and has been shown to have a variety of functions that range from the control Histone proteins are main components of the of gene transcription and DNA repair, to cell cycle nucleosome, the fundamental building block of regulation and nutrient stress response [8]. H3K36 chromatin in eukaryotic cells. In addition to play- methylated domains are associated with active ing a critical role in chromatin structure and transcription, and aberrant regulation of this chro- dynamics, histones undergo posttranslational matin mark has been linked to several cancers. modifications (PTMs) that provide mechanisms Particularly, histone mutations that affect H3K36 for mediating diverse cellular processes [1–3]. methylation were identified as likely drivers of PTMs or epigenetic marks are deposited, removed some types of pediatric cancers [9,10,11,12,13], and recognized by writers, erasers and readers, (Figure 1(b)). Genetic studies found that about respectively, which individually or in combination one fifth of high-grade astrocytomas (HGA) aris- initiate, halt, or propagate biological signals in the ing in the cerebral hemispheres of adolescents nucleus [4,5,6](Figure 1). Disruption of the intri- contain aberrations affecting K36, including H3 cate balance between activities of writers, erasers, mutations at G34 or loss of H3K36-specific writer, and readers is linked to a host of human diseases, the methyltransferase SETD2. Two bone cancers, including cancer and autoimmune, developmental, such as chondroblastoma and giant cell tumors and neurodegenerative disorders [7]. (GCT) of the bone that affect adolescents and One such histone modification that has inter- younger children, carry H3 mutations at K36 and sected at the cross-roads between normal and dis- G34, respectively. Importantly, these mutations are eased states is methylation of lysine 36 of histone the sole genetic alterations identified in these H3 (H3K36me). This chromatin mark is conserved tumors, and the tumor type and pattern suggest CONTACT Tatiana G. Kutateladze [email protected] Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Brian D. Strahl [email protected] Department of Biochemistry & Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Peter W. Lewis [email protected] Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA © 2018 Informa UK Limited, trading as Taylor & Francis Group 2 B. J. KLEIN ET AL. [14,15–19]. While the NSD1-3 enzymes mediate the bulk of H3K36me1 and H3K36me2 through- out the genome, SETD2 specially trimethylates H3K36 in a co-transcriptional manner through this enzyme’s ability to interact with the transcrib- ing RNA polymerase II (RNAPII) [20,21]. Consistent with the co-transcriptional role of SETD2, H3K36me3 is found almost exclusively in transcribed regions in yeast and mammals. In con- trast to SETD2, the NSD enzymes are not co- transcriptional and are known to methylate large stretches of intergenic regions across the genome that serve, at least in part, as domain boundaries that act to prevent the spread of polycomb- mediated H3 lysine 27 (H3K27) methylation [22]. Studies into the function of H3K36me reveal a wide range of activities, which include the sup- pressing histone exchange and intergenic tran- scription, promoting DNA repair, cell cycle progression and maintaining proper pre-mRNA splicing [8]. These functions, in large part, are Figure 1. Histone lysine PTMs and oncogenic mutations. (a) Schematic representation of writers, readers and erasers target- carried out by various reader complexes that ing lysine residues in histone tails of the nucleosome. (b) associate with this mark. Initially characterized in Residues of the H3 tail and mutations that have been linked yeast, H3K36 methylation was shown to recruit to cancer are colored green and red, respectively. and/or activate a number of chromatin-associated enzymes, including the Rpd3S deacetylase complex that the histone mutations themselves likely drive containing the Eaf3 chromodomain, ISW1b ATP- tumor formation in these neoplasms. dependent remodeling complex and the NuA3b Furthermore, the specificity of the histone gene acetyltransferase complex [23–27]. Although the affected in relation to patient age and tumor type function of NuA3b is less clear, the Rpd3S and or location further points toward a distinctive cell ISW1b complexes act to maintain a deacetylated of origin for these tumors and, subsequently, his- chromatin state within RNAPII transcribed tones are now referred to as ‘oncohistones’, since it regions that serves to enforce the suppression of is clear that these mutations act as classical cancer histone exchange and inappropriate transcription drivers. from occurring within these regions [28–32]. In this perspective, we highlight the latest From a cellular perspective, this process has been reports underlining the impact of oncohistone linked to life-span control, DNA double-stand mutations on writing and reading the H3K36me break repair, cell cycle progression, nutrient stress mark. We summarize the biological significance of response and, more recently, pre-mRNA splicing H3K36 methylation for normal cell processes and in budding yeast [33–42]. discuss recently proposed oncohistone-driven Like Set2 in yeast, H3K36me3 mediated by tumorigenic mechanisms. mammalian SETD2 is also known to recruit an Rpd3S-related HDAC complex that associates via the Eaf3 homolog MRG15; MRG15 also maintains H3K36 methylation and chromatin regulation reduced acetylation levels and functions in alter- In all mammals, H3K36 is methylated by a range native mRNA splicing [43,44]. Beyond HDACs, of lysine-specific enzymes, including SETD2, the SETD2 and the other H3K36 methyltransferases homolog of yeast Set2, NSD1, NSD2/MMSET/ have been shown to recruit a variety of other WHSC1, NSD3, SETMAR, SMYD2, and ASH1L chromatin-associated protein complexes that have EPIGENETICS 3 functions in transcription elongation, heterochro- structural evidence converge on the idea that matin formation, mRNA splicing, and DNA repair methionine substitution at particular lysines in [8]. For example, ZMYND11 was shown to bind H3 transform histones from serving as substrates H3.3K36me3 through its PWWP domain and to into potent orthosteric inhibitors of methyltrans- regulate pre-mRNA splicing and transcription ferases [60,62–68]. For example, H3K36M pep- elongation [45,46]. In addition, SETD2-mediated tides and H3K36M-containing nucleosomes H3K36me3 regulates the recruitment of the DNA inhibit catalytic activities of H3K36-specific methyltransferase DNMT3b to transcribed regions methyltransferases in vitro, and expression of also through a PWWP domain that controls gene H3K36M results in a global loss of H3K36 methy- body DNA methylation [47–49], which has lation in vivo [22,62,69,70]. remained somewhat elusive in function but may The oncogenic capacity of the H3K36M mutant contribute to suppression of intergenic transcrip- histone has recently been demonstrated in studies tion. Outside of transcriptional control, H3K36 with animal models. Introduction of the H3K36M methylation functions in homologous recombina- mutation into mesenchymal progenitor cells tion and mismatch repair through the recruitment causes a profound impairment of mesenchymal of LEDGF and MHS6, respectively [40,50,51]. differentiation. Furthermore, the H3K36M-expres- Intriguingly, H3K36 methylation also associates sing mesenchymal progenitor cells form tumors with the Tudor domains of PHF1/PHF19 of the resembling undifferentiated sarcomas in mice polycomb repressive complex 2 (PRC2) [52–59], xenograft studies. In addition to reduced which appears to function as a boundary element H3K36me2/3 levels, H3K36M-expressing tumors