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Qiang Zhou - One of the best experts on this subject based on the ideXlab platform.
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Structural basis for ELL2 and AFF4 activation of HIV-1 proviral transcription.
Nature communications, 2017Co-Authors: Ursula Schulze-gahmen, Qiang Zhou, Goran Stjepanovic, James H. HurleyAbstract:The intrinsically disordered scaffold proteins AFF1/4 and the transcription elongation factors ELL1/2 are core components of the super elongation complex required for HIV-1 proviral transcription. Here we report the 2.0-A resolution crystal structure of the human ELL2 C-terminal domain bound to its 50-residue binding site on AFF4, the ELLBow. The ELL2 domain has the same arch-shaped fold as the tight junction protein occludin. The ELLBow consists of an N-terminal helix followed by an extended hairpin that we refer to as the elbow joint, and occupies most of the concave surface of ELL2. This surface is important for the ability of ELL2 to promote HIV-1 Tat-mediated proviral transcription. The AFF4-ELL2 interface is imperfectly packed, leaving a cavity suggestive of a potential binding site for transcription-promoting small molecules.
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How the AFF1/4 scaffold recruits the elongation factor ELL2 to promote HIV-1 proviral transcription
2016Co-Authors: Ursula Schulze-gahmen, Qiang Zhou, Goran Stjepanovic, James H. HurleyAbstract:The intrinsically disordered scaffold proteins AFF1/4 and the transcription elongation factors ELL1/2 are core components of the superelongation complex required for HIV-1 proviral transcription. We determined the 2.0-A resolution crystal structure of the human ELL2 C-terminal domain bound to its 50-residue binding site on AFF4, the ELLBow. The ELL2 domain has the same arch-shaped fold as the tight junction protein occludin. The ELLBow consists of an N-terminal helix followed by an extended hairpin that we refer to as the elbow joint, and occupies most of the concave surface of ELL2. This surface is important for the ability of ELL2 to promote HIV-1 Tat-mediated proviral transcription. The AFF4-ELL2 interface is imperfectly packed, leaving a cavity suggestive of a potential binding site for transcription-promoting small molecules.
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how the AFF1 4 scaffold recruits the elongation factor ell2 to promote hiv 1 proviral transcription
bioRxiv, 2016Co-Authors: Ursula Schulzegahmen, Qiang Zhou, Goran Stjepanovic, James H. HurleyAbstract:The intrinsically disordered scaffold proteins AFF1/4 and the transcription elongation factors ELL1/2 are core components of the superelongation complex required for HIV-1 proviral transcription. We determined the 2.0-A resolution crystal structure of the human ELL2 C-terminal domain bound to its 50-residue binding site on AFF4, the ELLBow. The ELL2 domain has the same arch-shaped fold as the tight junction protein occludin. The ELLBow consists of an N-terminal helix followed by an extended hairpin that we refer to as the elbow joint, and occupies most of the concave surface of ELL2. This surface is important for the ability of ELL2 to promote HIV-1 Tat-mediated proviral transcription. The AFF4-ELL2 interface is imperfectly packed, leaving a cavity suggestive of a potential binding site for transcription-promoting small molecules.
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A Minor Subset of Super Elongation Complexes Plays a Predominant Role in Reversing HIV-1 Latency
Molecular and cellular biology, 2016Co-Authors: Qiang ZhouAbstract:Promoter-proximal pausing by RNA polymerase II (Pol II) is a key rate-limiting step in HIV-1 transcription and latency reversal. The viral Tat protein recruits human super elongation complexes (SECs) to paused Pol II to overcome this restriction. Despite the recent progress in understanding the functions of different subsets of SECs in controlling cellular and Tat-activated HIV transcription, little is known about the SEC subtypes that help reverse viral latency in CD4(+) T cells. Here, we used the CRISPR-Cas9 genome-editing tool to knock out the gene encoding the SEC subunit ELL2, AFF1, or AFF4 in Jurkat/2D10 cells, a well-characterized HIV-1 latency model. Depletion of these proteins drastically reduced spontaneous and drug-induced latency reversal by suppressing HIV-1 transcriptional elongation. Surprisingly, a low-abundance subset of SECs containing ELL2 and AFF1 was found to play a predominant role in cooperating with Tat to reverse latency. By increasing the cellular level/activity of these Tat-friendly SECs, we could potently activate latent HIV-1 without using any drugs. These results implicate the ELL2/AFF1-SECs as an important target in the future design of a combinatorial therapeutic approach to purge latent HIV-1.
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gene target specificity of the super elongation complex sec family how hiv 1 tat employs selected sec members to activate viral transcription
Nucleic Acids Research, 2015Co-Authors: Zichong Li, Huasong Lu, Wei Zhang, Ursula Schulzegahmen, Qiang ZhouAbstract:The AF4/FMR2 proteins AFF1 and AFF4 act as a scaffold to assemble the Super Elongation Complex (SEC) that strongly activates transcriptional elongation of HIV-1 and cellular genes. Although they can dimerize, it is unclear whether the dimers exist and function within a SEC in vivo. Furthermore, it is unknown whether AFF1 and AFF4 function similarly in mediating SEC-dependent activation of diverse genes. Providing answers to these questions, our current study shows that AFF1 and AFF4 reside in separate SECs that display largely distinct gene target specificities. While the AFF1-SEC is more potent in supporting HIV-1 transactivation by the viral Tat protein, the AFF4-SEC is more important for HSP70 induction upon heat shock. The functional difference between AFF1 and AFF4 in Tat-transactivation has been traced to a single amino acid variation between the two proteins, which causes them to enhance the affinity of Tat for P-TEFb, a key SEC component, with different efficiency. Finally, genome-wide analysis confirms that the genes regulated by AFF1-SEC and AFF4-SEC are largely non-overlapping and perform distinct functions. Thus, the SEC represents a family of related complexes that exist to increase the regulatory diversity and gene control options during transactivation of diverse cellular and viral genes.
Y. Yogo - One of the best experts on this subject based on the ideXlab platform.
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JC virus genotypes in a Taiwan aboriginal tribe (Bunun): implications for its population history^*
Archives of Virology, 1999Co-Authors: D. Chang, C. Sugimoto, M. Wang, R.-t. Tsai, Y. YogoAbstract:The origin of Taiwanese aborigines remains obscure; it has been speculated that they may be from either mainland China or southeastern Asia. We used the JCV genotyping method to elucidate the origin of Bunun aborigines who now live in central mountain areas of Taiwan. We found that Bunun aborigines carried two major (B1-Aff2 and CY) and two minor JCV genotypes (B1-AFF1 and SC). This was contrasted with the JCV genotype profile in modern Taiwanese: one major (SC) and two minor genotypes (CY and B1-AFF1). It thus appears that B1-Aff2 and CY are indigenous to the Bunun tribe. B1-Aff2 was first identified in this study as a discrete cluster that contained only Bunun and Philippine JCV isolates and that was closely related to B1-AFF1, one of the three common JCV genotypes in China. CY predominates in North China, while SC predominates in South China and southeastern Asia. The present findings suggest that the Bunun tribe is an admixture of two ethnic groups, one carrying B1-Aff2 and the other carrying CY. In other words, it is likely that the Bunun tribe was established by two waves of immigrations from mainland Asia, predating those by southern Chinese which began in the 17th century.
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JC virus genotypes in a Taiwan aboriginal tribe (Bunun): implications for its population history *
Archives of virology, 1999Co-Authors: D. Chang, C. Sugimoto, M. Wang, R.-t. Tsai, Y. YogoAbstract:The origin of Taiwanese aborigines remains obscure; it has been speculated that they may be from either mainland China or southeastern Asia. We used the JCV genotyping method to elucidate the origin of Bunun aborigines who now live in central mountain areas of Taiwan. We found that Bunun aborigines carried two major (B1-Aff2 and CY) and two minor JCV genotypes (B1-AFF1 and SC). This was contrasted with the JCV genotype profile in modern Taiwanese: one major (SC) and two minor genotypes (CY and B1-AFF1). It thus appears that B1-Aff2 and CY are indigenous to the Bunun tribe. B1-Aff2 was first identified in this study as a discrete cluster that contained only Bunun and Philippine JCV isolates and that was closely related to B1-AFF1, one of the three common JCV genotypes in China. CY predominates in North China, while SC predominates in South China and southeastern Asia. The present findings suggest that the Bunun tribe is an admixture of two ethnic groups, one carrying B1-Aff2 and the other carrying CY. In other words, it is likely that the Bunun tribe was established by two waves of immigrations from mainland Asia, predating those by southern Chinese which began in the 17th century.
D. Chang - One of the best experts on this subject based on the ideXlab platform.
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JC virus genotypes in a Taiwan aboriginal tribe (Bunun): implications for its population history^*
Archives of Virology, 1999Co-Authors: D. Chang, C. Sugimoto, M. Wang, R.-t. Tsai, Y. YogoAbstract:The origin of Taiwanese aborigines remains obscure; it has been speculated that they may be from either mainland China or southeastern Asia. We used the JCV genotyping method to elucidate the origin of Bunun aborigines who now live in central mountain areas of Taiwan. We found that Bunun aborigines carried two major (B1-Aff2 and CY) and two minor JCV genotypes (B1-AFF1 and SC). This was contrasted with the JCV genotype profile in modern Taiwanese: one major (SC) and two minor genotypes (CY and B1-AFF1). It thus appears that B1-Aff2 and CY are indigenous to the Bunun tribe. B1-Aff2 was first identified in this study as a discrete cluster that contained only Bunun and Philippine JCV isolates and that was closely related to B1-AFF1, one of the three common JCV genotypes in China. CY predominates in North China, while SC predominates in South China and southeastern Asia. The present findings suggest that the Bunun tribe is an admixture of two ethnic groups, one carrying B1-Aff2 and the other carrying CY. In other words, it is likely that the Bunun tribe was established by two waves of immigrations from mainland Asia, predating those by southern Chinese which began in the 17th century.
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JC virus genotypes in a Taiwan aboriginal tribe (Bunun): implications for its population history *
Archives of virology, 1999Co-Authors: D. Chang, C. Sugimoto, M. Wang, R.-t. Tsai, Y. YogoAbstract:The origin of Taiwanese aborigines remains obscure; it has been speculated that they may be from either mainland China or southeastern Asia. We used the JCV genotyping method to elucidate the origin of Bunun aborigines who now live in central mountain areas of Taiwan. We found that Bunun aborigines carried two major (B1-Aff2 and CY) and two minor JCV genotypes (B1-AFF1 and SC). This was contrasted with the JCV genotype profile in modern Taiwanese: one major (SC) and two minor genotypes (CY and B1-AFF1). It thus appears that B1-Aff2 and CY are indigenous to the Bunun tribe. B1-Aff2 was first identified in this study as a discrete cluster that contained only Bunun and Philippine JCV isolates and that was closely related to B1-AFF1, one of the three common JCV genotypes in China. CY predominates in North China, while SC predominates in South China and southeastern Asia. The present findings suggest that the Bunun tribe is an admixture of two ethnic groups, one carrying B1-Aff2 and the other carrying CY. In other words, it is likely that the Bunun tribe was established by two waves of immigrations from mainland Asia, predating those by southern Chinese which began in the 17th century.
Ali Shilatifard - One of the best experts on this subject based on the ideXlab platform.
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Acute perturbation strategies in interrogating RNA polymerase II elongation factor function in gene expression.
Genes & development, 2021Co-Authors: Bin Zheng, Yuki Aoi, Avani P Shah, Marta Iwanaszko, Siddhartha Das, Emily J Rendleman, Didi Zha, Nabiha Khan, Edwin R Smith, Ali ShilatifardAbstract:The regulation of gene expression catalyzed by RNA polymerase II (Pol II) requires a host of accessory factors to ensure cell growth, differentiation, and survival under environmental stress. Here, using the auxin-inducible degradation (AID) system to study transcriptional activities of the bromodomain and extraterminal domain (BET) and super elongation complex (SEC) families, we found that the CDK9-containing BRD4 complex is required for the release of Pol II from promoter-proximal pausing for most genes, while the CDK9-containing SEC is required for activated transcription in the heat shock response. By using both the proteolysis targeting chimera (PROTAC) dBET6 and the AID system, we found that dBET6 treatment results in two major effects: increased pausing due to BRD4 loss, and reduced enhancer activity attributable to BRD2 loss. In the heat shock response, while auxin-mediated depletion of the AFF4 subunit of the SEC has a more severe defect than AFF1 depletion, simultaneous depletion of AFF1 and AFF4 leads to a stronger attenuation of the heat shock response, similar to treatment with the SEC inhibitor KL-1, suggesting a possible redundancy among SEC family members. This study highlights the usefulness of orthogonal acute depletion/inhibition strategies to identify distinct and redundant biological functions among Pol II elongation factor paralogs.
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The super elongation complex family of RNA polymerase II elongation factors: Gene target specificity and transcriptional output
Molecular and cellular biology, 2012Co-Authors: Zhuojuan Luo, Chengqi Lin, Erin M. Guest, Alexander S. Garrett, Nima Mohaghegh, Selene K. Swanson, Stacy A. Marshall, Laurence Florens, Michael P. Washburn, Ali ShilatifardAbstract:The elongation stage of transcription is highly regulated in metazoans. We previously purified the AFF1- and AFF4-containing super elongation complex (SEC) as a major regulator of development and cancer pathogenesis. Here, we report the biochemical isolation of SEC-like 2 (SEC-L2) and SEC-like 3 (SEC-L3) containing AFF2 and AFF3 in association with P-TEFb, ENL/MLLT1, and AF9/MLLT3. The SEC family members demonstrate high levels of polymerase II (Pol II) C-terminal domain kinase activity; however, only SEC is required for the proper induction of the HSP70 gene upon stress. Genome-wide mRNA-Seq analyses demonstrated that SEC-L2 and SEC-L3 control the expression of different subsets of genes, while AFF4/SEC plays a more dominant role in rapid transcriptional induction in cells. MYC is one of the direct targets of AFF4/SEC, and SEC recruitment to the MYC gene regulates its expression in different cancer cells, including those in acute myeloid or lymphoid leukemia. These findings suggest that AFF4/SEC could be a potential therapeutic target for the treatment of leukemia or other cancers associated with MYC overexpression.
M. Wang - One of the best experts on this subject based on the ideXlab platform.
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JC virus genotypes in a Taiwan aboriginal tribe (Bunun): implications for its population history^*
Archives of Virology, 1999Co-Authors: D. Chang, C. Sugimoto, M. Wang, R.-t. Tsai, Y. YogoAbstract:The origin of Taiwanese aborigines remains obscure; it has been speculated that they may be from either mainland China or southeastern Asia. We used the JCV genotyping method to elucidate the origin of Bunun aborigines who now live in central mountain areas of Taiwan. We found that Bunun aborigines carried two major (B1-Aff2 and CY) and two minor JCV genotypes (B1-AFF1 and SC). This was contrasted with the JCV genotype profile in modern Taiwanese: one major (SC) and two minor genotypes (CY and B1-AFF1). It thus appears that B1-Aff2 and CY are indigenous to the Bunun tribe. B1-Aff2 was first identified in this study as a discrete cluster that contained only Bunun and Philippine JCV isolates and that was closely related to B1-AFF1, one of the three common JCV genotypes in China. CY predominates in North China, while SC predominates in South China and southeastern Asia. The present findings suggest that the Bunun tribe is an admixture of two ethnic groups, one carrying B1-Aff2 and the other carrying CY. In other words, it is likely that the Bunun tribe was established by two waves of immigrations from mainland Asia, predating those by southern Chinese which began in the 17th century.
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JC virus genotypes in a Taiwan aboriginal tribe (Bunun): implications for its population history *
Archives of virology, 1999Co-Authors: D. Chang, C. Sugimoto, M. Wang, R.-t. Tsai, Y. YogoAbstract:The origin of Taiwanese aborigines remains obscure; it has been speculated that they may be from either mainland China or southeastern Asia. We used the JCV genotyping method to elucidate the origin of Bunun aborigines who now live in central mountain areas of Taiwan. We found that Bunun aborigines carried two major (B1-Aff2 and CY) and two minor JCV genotypes (B1-AFF1 and SC). This was contrasted with the JCV genotype profile in modern Taiwanese: one major (SC) and two minor genotypes (CY and B1-AFF1). It thus appears that B1-Aff2 and CY are indigenous to the Bunun tribe. B1-Aff2 was first identified in this study as a discrete cluster that contained only Bunun and Philippine JCV isolates and that was closely related to B1-AFF1, one of the three common JCV genotypes in China. CY predominates in North China, while SC predominates in South China and southeastern Asia. The present findings suggest that the Bunun tribe is an admixture of two ethnic groups, one carrying B1-Aff2 and the other carrying CY. In other words, it is likely that the Bunun tribe was established by two waves of immigrations from mainland Asia, predating those by southern Chinese which began in the 17th century.