Histone H3.3 and Cancer: a Potential Reader Connection
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Histone H3.3 and cancer: A potential reader connection Fei Lana,b,1 and Yang Shic,d,1 aKey Laboratory of Epigenetics of Shanghai Ministry of Education, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China; bKey Laboratory of Birth Defect, Children’s Hospital of Fudan University, Shanghai 201102, China; cDepartment of Cell Biology, Harvard Medical School, Boston, MA 02115; and dDivision of Newborn Medicine, Boston Children’s Hospital, Boston MA 02115 Edited by Donald W. Pfaff, The Rockefeller University, New York, NY, and approved November 7, 2014 (received for review October 2, 2014) The building block of chromatin is nucleosome, which consists of G34R/G34V/G34W/G34L, and K36M. Although both H3F3A and 146 base pairs of DNA wrapped around a histone octamer com- H3F3B encode H3.3 with identical amino acid sequences, the posed of two copies of histone H2A, H2B, H3, and H4. Significantly, H3.3K36M mutation occurs predominantly in H3F3B whereas the the somatic missense mutations of the histone H3 variant, H3.3, are other mutations are almost exclusive to H3F3A (9). Furthermore, associated with childhood and young-adult tumors, such as pediat- these different mutations also appear to segregate with distinct ric high-grade astrocytomas, as well as chondroblastoma and giant- types of tumors. For instance, the K27M mutation has been found cell tumors of the bone. The mechanisms by which these histone only in pediatric diffuse intrinsic pontine glioma (DIPG) and high- mutations cause cancer are by and large unclear. Interestingly, two grade astrocytomas primarily restricted to midline locations (spi- recent studies identified BS69/ZMYND11, which was proposed to be nal cord, thalamus, pons, brainstem) in children and younger a candidate tumor suppressor, as a specific reader for a modified adults (11–17). The majority of K36M mutation has been found form of H3.3 (H3.3K36me3). Importantly, some H3.3 cancer muta- in chondroblastoma, and to a lesser extent, in clear-cell chon- tions are predicted to abrogate the H3.3K36me3/BS69 interaction, drosarcoma (9). The G34R/V mutations predominantly associate suggesting that this interaction may play an important role in with pediatric glioblastoma multiforme (GBM) in the cerebral tumor suppression. These new findings also raise the question of hemispheres (11, 12, 18, 19), and in some very rare cases, in oste- whether H3.3 cancer mutations may lead to the disruption and/or osarcoma (9). Interestingly, two different substitutions at the same gain of interactions of additional cellular factors that contribute to amino acid position, G34W and G34L, have been found only in tumorigenesis. giant-cell tumor of bone (9). It remains to be determined whether differential association of these H3.3 mutations with histone | H3.3 | H3.3K36me3 | cancer | BS69 differential cancer types may imply disparate underlying mo- lecular mechanisms. he histone H3 variant, H3.3, differs from the canonical his- Recent studies have begun to address the mechanism by which Ttone H3 (H3.2 and H3.1) by only 4 and 5 amino acids, re- H3.3 mutations may cause cancer. It has been demonstrated that spectively. With the exception of serine 31 located in the H3.3 the H3.3K27M mutation affects not only the methylation po- tail region, the rest of the amino acid difference resides in the tential on the mutated histone tail but also global methylation of nucleosome core, which dictates the differential recognition of H3K27me3 in cell-culture models as well as in the primary the H3.3 variant versus the canonical histone H3 by different tumors (19–21). Supporting this finding, a recent study in Dro- histone chaperones as well as its mode of incorporation into the sophila also found that the H3.3K27M ectopic expression phe- chromatin. The canonical histone H3 proteins are incorporated nocopies PRC2 mutants and causes loss of global H3K27me3 into chromatin via the histone chaperone CAF-1 (chromatin and depression of PRC2 target genes (22). In the study from assembly factor 1) at S phase in a replication-dependent manner Lewis et al., H3.3K36M was also shown to cause a global re- (1). In contrast, H3.3 is incorporated into chromatin by HIRA duction of H3K36me3 (19). Cross talk between these mutations (histone regulator A) and DAXX (death domain-associated and the nearby modifications has also been observed. For in- protein)/ATRX (alpha thalassemia/mental retardation syndrome stance, G34R/V mutations have been found to cause a significant X-linked protein), respectively, in a replication-independent loss of H3.3K36me3 only in cis (19), suggesting that these muta- manner (1–3), suggesting that H3.3 may play a regulatory role in tions may differentially influence the affected epigenomes. Sub- many chromatin-templated processes outside of the S phase of sequent studies also showed that K27M and G34R/V mutations are the cell cycle, including transcription. Consistently, H3.3 has mutually exclusive in tumors and are associated with distinct gene been found at gene bodies and promoters of transcriptionally expression and DNA methylation profiles (11, 12). The clinical active genes as well as gene regulatory elements, such as significance of these findings, however, remains to be de- enhancers (1, 4, 5). More recently, it has been shown that the termined. Taken together, these recent exciting findings sug- H3.3-containing nucleosomes are compromised in their ability gest that H3.3 mutations may play an oncogenic driver role by to form compact structure in vitro and that the H3.3 genomic reshaping the epigenomes through alterations of either the distribution correlates well with DNase I-sensitive regions, local or global histone methylation patterns. Although much suggesting a preferential association with open chromatin remains to be learned regarding the mechanism by which these environment in vivo (6). Interestingly, H3.3 has also been mutations cause cancer, two recent studies unexpectedly found found at pericentromeric and telomeric regions, where its an H3.3K36me3-specific reader, BS69/ZMYND11, which may deposition is largely dependent on the DAXX/ATRX chap- erone system; however, the function of H3.3 at these regions remains unclear (7). This paper results from the Arthur M. Sackler Colloquium of the National Academy of Although H3.3 represents only a small portion of the total Sciences, “Epigenetic Changes in the Developing Brain: Effects on Behavior,” held March 28–29, 2014, at the National Academy of Sciences in Washington, DC. The complete pro- cellular histone H3 pool (8), emerging evidence suggests that H3.3 gram and video recordings of most presentations are available on the NAS website at carries biological information that is distinct from its counterparts, www.nasonline.org/Epigenetic_changes. H3.1 and H3.2. This notion is best exemplified by the exciting Author contributions: F.L. and Y.S. wrote the paper. recent findings of recurring heterozygous mutations in H3F3A and Conflict of interest statement: Y.S. is a cofounder of Constellation Pharmaceutical, Inc. H3F3B, the only two genes in mammals that encode H3.3, that are and a member of its scientific advisory board. associated with a number of pediatric cancers, including pediatric This article is a PNAS Direct Submission. and young-adult high-grade astrocytomas, chondroblastoma, and 1To whom correspondence may be addressed. Email: [email protected] or fei_lan@ giant-cell tumor of bone (9–11). These mutations include K27M, fudan.edu.cn. 6814–6819 | PNAS | June 2, 2015 | vol. 112 | no. 22 www.pnas.org/cgi/doi/10.1073/pnas.1418996111 Downloaded by guest on September 30, 2021 PAPER provide a new avenue to explore H3.3 biology as well as its cancer BS69 BROMO-PWWP Domains Read H3.3K36me3 COLLOQUIUM connection (23, 24). In these two recent studies (23, 24), the BS69 PWWP domain was identified as a specific reader for the K36 trimethylation on BS69 (also Known as ZMYND11) histone variant H3.3 (H3.3K36me3) (Fig. 1). In both studies, the BS69 was originally identified as an interacting protein of the authors used an array of methylated and unmethylated histone adenoviral E1A oncoprotein and a suppressor of the trans- peptides and demonstrated that, surprisingly, BS69 preferentially activating function of E1A and has thus been suggested to recognizes H3.3K36me3. This highly specific recognition is sen- function as a transcriptional repressor and a candidate tumor sitive to both the methyl level on lysine 36: i.e., BS69 binds to suppressor (25–27). The architecture of BS69 is quite interesting; H3.3K36me3, but much less to H3.3K36me0/1/2, as well as the the N-terminal two thirds of BS69 contains three tandemly adjacent residues, S31 on H3.3 vs. A31 on H3.1/2 (23, 24). Using arranged, putative chromatin recognition modules: namely PHD, a cocrystallization approach, the Wen et al. study provided at the BROMO, and PWWP domains (Fig. 1). The C terminus of BS69 atomic level mechanistic understanding of how the BS69 reader contains a zinc-binding motif, the MYND domain, which func- modalities discriminate H3.3K36me3 from H3.1K36me3. In- tions as a protein–protein interaction surface, which mediates terestingly, the recognition of H3.3K36me3 by BS69 involves not interactions of BS69 with transcription factors and chromatin only the PWWP but also the adjacent BROMO domain (23). (26–28) (Fig. 1). Compared with the MYND domain, essentially Specifically, the H3.3-dependent recognition is mediated by the “ ” nothing was known about the three N-terminal putative chro- encapsulation of the H3.3-specific S31 residue in a composite matin readers. Previous studies indicated that PHD and BROMO pocket formed by the tandem BROMO-PWWP domains of BS69. S31 is a critical contact that is lacking in H3.1/2, thus domains are protein modalities that mainly recognize methylated explaining the preference of BS69 toward H3.3K36me3 (23).