Recognition of modified histones by “reader” proteins plays a critical role in the regulation of chromatin1. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions following RNA polymerase II (Pol II) elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state thus suppressing cryptic transcription2. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies3. Here we show that the candidate tumor suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates Pol II elongation. Structural studies reveal that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific “Ser31” residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. ChIP-sequencing analyses reveal a genome-wide colocalization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription corepressor via modulating Pol II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumor cell growth; low expression level of ZMYND11 in breast cancer patients correlates with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumor formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone variant-mediated transcription elongation control to tumor suppression.
Recognition of modified histones by “reader” proteins constitutes a key mechanism regulating diverse chromatin-associated processes important for normal and neoplastic development. We recently identified the YEATS domain as a novel acetyllysine-binding module; however, the functional importance of YEATS domain-containing proteins in human cancer remains largely unknown. Here, we show that the YEATS2 gene is highly amplified in human non-small cell lung cancer (NSCLC) and is required for cancer cell growth and survival. YEATS2 binds to acetylated histone H3 via its YEATS domain. The YEATS2-containing ATAC complex co-localizes with H3K27 acetylation (H3K27ac) on the promoters of actively transcribed genes. Depletion of YEATS2 or disruption of the interaction between its YEATS domain and acetylated histones reduces the ATAC complex-dependent promoter H3K9ac levels and deactivates the expression of essential genes. Taken together, our study identifies YEATS2 as a histone H3K27ac reader that regulates a transcriptional program essential for NSCLC tumorigenesis.
We have characterized previously the nuclear matrix protein/scaffold attachment factor (SAFB) as an estrogen receptor corepressor and as a potential tumor suppressor gene in breast cancer. A search of the human genome for other potential SAFB family members revealed that KIAA00138 (now designated as SAFB2) has high homology to SAFB (now designated as SAFB1). SAFB1 and SAFB2 are mapped adjacent to each other on chromosome 19p13.3 and are arranged in a bidirectional divergent configuration (head to head), being separated by a short (<500 bp) GC-rich intergenic region that can function as a bidirectional promoter. SAFB1 and SAFB2 share common functions but also have unique properties. As shown previously for SAFB1, SAFB2 functions as an estrogen receptor corepressor, and its overexpression results in inhibition of proliferation. SAFB1 and SAFB2 interact directly through a C-terminal domain, resulting in additive repression activity. They are coexpressed in a number of tissues, but unlike SAFB1, which is exclusively nuclear, SAFB2 is found in the cytoplasm as well as the nucleus. Consistent with its cytoplasmic localization, we detected an interaction between SAFB2 and vinexin, a protein involved in linking signaling to the cytoskeleton. Our findings suggest that evolutionary duplication of the SAFB gene has allowed it to retain crucial functions, but also to gain novel functions in the cytoplasm and/or nucleus.Scaffold attachment factor B (SAFB, 1 also named HET and HAP in the literature) was originally identified based on its ability to bind to scaffold/matrix attachment regions (1) and as a protein binding to the small heat shock protein hsp27 gene promoter (2). SAFB is a large protein (130 kDa) with a number of putative functional domains. The function of many of these domains is still unclear but can be inferred from the roles of similar domains in other proteins. The N terminus contains an SAF box (3) (also called an SAP domain (4)), which is a homeodomain-like DNA binding motif. This motif is believed to play a role in chromatin organization and specifically in organizing the interaction between nuclear matrix proteins and scaffold/ matrix attachment regions. SAF boxes are found in proteins involved in very diverse processes such as transcription, RNA processing, apoptotic chromatin degradation, and DNA repair (3). Amino acids 409 -484 harbor an RNA recognition motif (RRM), which is often found in mRNA-processing proteins. SAFB can interact with a number of proteins from the RNAprocessing machinery, such as AUF1/hnRNP D, hnRNP A1, htra2-1, ASF/SF2, SRp30c, and CLK2 (5-7). Consistent with this, SAFB is able to alter the splice site selection of an E1A minigene (7). Because SAFB was also shown to interact with the C-terminal domain of RNA polymerase II, it has been suggested to be part of a "transcriptosome" complex, coupling transcription and RNA processing (7). SAFB has a nuclear localization signal (NLS), and using biochemical fractionation experiments, we and others have shown that SAFB is a nuclear protei...
Histone acetylation is associated with active transcription in eukaryotic cells. It helps to open up the chromatin by neutralizing the positive charge of histone lysine residues and providing binding platforms for "reader" proteins. The bromodomain (BRD) has long been thought to be the sole protein module that recognizes acetylated histones. Recently, we identified the YEATS domain of AF9 (ALL1 fused gene from chromosome 9) as a novel acetyl-lysine-binding module and showed that the ENL (eleven-nineteen leukemia) YEATS domain is an essential acetyl-histone reader in acute myeloid leukemias. The human genome encodes four YEATS domain proteins, including GAS41, a component of chromatin remodelers responsible for H2A.Z deposition onto chromatin; however, the importance of the GAS41 YEATS domain in human cancer remains largely unknown. Here we report that is frequently amplified in human non-small cell lung cancer (NSCLC) and is required for cancer cell proliferation, survival, and transformation. Biochemical and crystal structural studies demonstrate that GAS41 binds to histone H3 acetylated on H3K27 and H3K14, a specificity that is distinct from that of AF9 or ENL. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) analyses in lung cancer cells reveal that GAS41 colocalizes with H3K27ac and H3K14ac on the promoters of actively transcribed genes. Depletion of GAS41 or disruption of the interaction between its YEATS domain and acetylated histones impairs the association of histone variant H2A.Z with chromatin and consequently suppresses cancer cell growth and survival both in vitro and in vivo. Overall, our study identifies GAS41 as a histone acetylation reader that promotes histone H2A.Z deposition in NSCLC.
Estrogen receptor α (ERα) has an established role in promoting breast cancer. Transcriptional activation by ERα is a complex and multistep process, and it is influenced by coactivator and corepressor proteins that can either positively or negatively modulate ERα-mediated transcriptional activity. Corepressors are proposed to provide a counterbalance to the estrogen-induced transactivation, and represent a potential mechanism employed by the cell to regulate hormonal responses. In this review, we present evidence from tissue culture, animal and clinical studies, supporting the hypothesis that corepressors are crucial regulators of ERα-mediated action, and that their loss could promote breast cancer development and resistance to endocrine therapy. We propose that ERα corepressors play an important biological role by controlling the magnitude of the estrogen response, mediating antiestrogen inhibition of ERα, repressing DNA-bound ERα in the absence of the ligand, and conferring active repression of ERα-downregulated genes. Different ERα corepressors regulate steroid receptor activity through a variety of mechanisms, including formation of multiprotein complexes that are able to affect chromatin remodeling, histone deacetylation, or basal transcription. Other mechanisms include competition with coactivators, interference with DNA binding and ERα homodimerization, alteration of ERα stability, sequestration of ERα in the cytoplasm, and effects on RNA processing. Most ERα corepressors can control the receptor's activity through more than one mechanism, and it is possible that the synergy between different pathways cooperates to fully inhibit ERα transcriptional activity, and create an integrated response to a variety of different cellular signaling pathways. We will discuss the role of corepressors in tumor suppression and the link they might present between ERα regulation and DNA repair. Finally, we will discuss major challenges in the field and speculate on the exciting findings that await us in the next few years.
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