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Qiang Zhou - One of the best experts on this subject based on the ideXlab platform.
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host cell factors stimulate hiv 1 transcription by antagonizing substrate binding function of siah1 ubiquitin ligase to stabilize transcription elongation factor ell2
Nucleic Acids Research, 2020Co-Authors: Yuhua Xue, Xiang Gao, Qiang ZhouAbstract:The Siah1 and Siah2 ubiquitin ligases are implicated in diverse biological processes ranging from cellular stress responses, signaling to transcriptional regulation. A key substrate of Siah1 is ELL2, which undergoes proteolysis upon polyubiquitination. ELL2 stimulates transcriptional elongation and is a subunit of the Super Elongation Complex (SEC) essential for HIV-1 transactivation. Previously, multiple transcriptional and post-translational mechanisms are reported to control Siah's expression and activity. Here we show that the activity of Siah1/2 can also be suppressed by host cell factor 1 (HCF1), and the hitherto poorly characterized HCF2, which themselves are not degraded but can bind and block the substrate-binding domain (SBD) of Siah1/2 to prevent their autoubiquitination and trans-ubiquitination of downstream targets including ELL2. This effect stabilizes ELL2 and enhances the ELL2-SEC formation for robust HIV-1 transactivation. Thus, our study not only identifies HCF1/2 as novel activators of HIV-1 transcription through inhibiting Siah1 to stabilize ELL2, but also reveals the SBD of Siah1/2 as a previously unrecognized new target for HCF1/2 to exert this inhibition.
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reiterative enrichment and authentication of crispri targets react identifies the proteasome as a key contributor to hiv 1 latency
PLOS Pathogens, 2019Co-Authors: Leonard Chavez, Rebecca Hoh, Steven G Deeks, Satish K Pillai, Qiang ZhouAbstract:The establishment of HIV-1 latency gives rise to persistent chronic infection that requires life-long treatment. To reverse latency for viral eradiation, the HIV-1 Tat protein and its associated ELL2-containing Super Elongation Complexes (ELL2-SECs) are essential to activate HIV-1 transcription. Despite efforts to identify effective latency-reversing agents (LRA), avenues for exposing latent HIV-1 remain inadequate, prompting the need to identify novel LRA targets. Here, by conducting a CRISPR interference-based screen to reiteratively enrich loss-of-function genotypes that increase HIV-1 transcription in latently infected CD4+ T cells, we have discovered a key role of the proteasome in maintaining viral latency. Downregulating or inhibiting the proteasome promotes Tat-transactivation in cell line models. Furthermore, the FDA-approved proteasome inhibitors bortezomib and carfilzomib strongly synergize with existing LRAs to reactivate HIV-1 in CD4+ T cells from antiretroviral therapy-suppressed individuals without inducing cell activation or proliferation. Mechanistically, downregulating/inhibiting the proteasome elevates the levels of ELL2 and ELL2-SECs to enable Tat-transactivation, indicating the proteasome-ELL2 axis as a key regulator of HIV-1 latency and promising target for therapeutic intervention.
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The PARP1-Siah1 Axis Controls HIV-1 Transcription and Expression of Siah1 Substrates
'Elsevier BV', 2018Co-Authors: Rongdiao Liu, Geng Yang, Qiang ZhouAbstract:Summary: Recent studies have revealed a key role of PARP1 that catalyzes the poly-ADP-ribosylation (PARylation) of substrates in regulating gene transcription. We show here that HIV-1 transcriptional activation also requires PARP1 activity. Because efficient HIV-1 transactivation is known to depend on the ELL2-containing super elongation complex (SEC), we investigated the functional relationship between PARP1 and ELL2-SEC in HIV-1 transcriptional control. We show that PARP1 elevates ELL2 protein levels to form more ELL2-SEC in cells. This effect is caused by PARP1’s suppression of expression of Siah1, an E3 ubiquitin ligase for ELL2, at both mRNA and protein levels. At the mRNA level, PARP1 coordinates with the co-repressor NCoR to suppress Siah1 transcription. At the protein level, PARP1 promotes Siah1 proteolysis, likely through inducing PARylation-dependent ubiquitination (PARdU) of Siah1. Thus, a PARP1-Siah1 axis activates HIV-1 transcription and controls the expression of ELL2 and other Siah1 substrates. : Yu et al. reveal a critical role for a PARP1-Siah1 axis in controlling HIV-1 viral transcription. The axis increases cellular levels of the transcription factor ELL2 and its associated SEC complex that is required for robust HIV-1 transcription. Keywords: PARP1, Poly(ADP-Ribosyl)ation, PARylation, PARylation-dependent ubiquitination, PARdU, E3 ubiquitin ligase Siah1, HIV-1 transcription, ELL2, super elongation complex, SE
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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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hiv 1 tat and host aff4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of hiv 1 transcription
Molecular Cell, 2010Co-Authors: Min Liu, Yuhua Xue, Nevan J. Krogan, Tom Alber, Seemay Chou, Joanne Hsu, Alma L Burlingame, Qiang ZhouAbstract:Recruitment of the P-TEFb kinase by HIV-1 Tat to the viral promoter triggers the phosphorylation and escape of RNA polymerase II from promoter-proximal pausing. It is unclear, however, if Tat recruits additional host factors that further stimulate HIV-1 transcription. Using a sequential affinity-purification scheme, we have identified human transcription factors/coactivators AFF4, ENL, AF9, and elongation factor ELL2 as components of the Tat-P-TEFb complex. Through the bridging functions of Tat and AFF4, P-TEFb and ELL2 combine to form a bifunctional elongation complex that greatly activates HIV-1 transcription. Without Tat, AFF4 can mediate the ELL2-P-TEFb interaction, albeit inefficiently. Tat overcomes this limitation by bringing more ELL2 to P-TEFb and stabilizing ELL2 in a process that requires active P-TEFb. The ability of Tat to enable two different classes of elongation factors to cooperate and coordinate their actions on the same polymerase enzyme explains why Tat is such a powerful activator of HIV-1 transcription.
Holly K. Tabor - One of the best experts on this subject based on the ideXlab platform.
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spectrum of MLL2 alr mutations in 110 cases of kabuki syndrome
American Journal of Medical Genetics Part A, 2011Co-Authors: Mark C Hannibal, Jeffrey E Ming, Sarah B Ng, Margaret J Mcmillin, Heidi I S Gildersleeve, Abigail W Bigham, Kati J Buckingham, Anita E. Beck, Holly K. TaborAbstract:Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.
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exome sequencing identifies MLL2 mutations as a cause of kabuki syndrome
Nature Genetics, 2010Co-Authors: Abigail W Bigham, Mark C Hannibal, Margaret J Mcmillin, Heidi I S Gildersleeve, Kati J Buckingham, Anita E. Beck, Holly K. TaborAbstract:We demonstrate the successful application of exome sequencing to discover a gene for an autosomal dominant disorder, Kabuki syndrome (OMIM%147920). We subjected the exomes of ten unrelated probands to massively parallel sequencing. After filtering against existing SNP databases, there was no compelling candidate gene containing previously unknown variants in all affected individuals. Less stringent filtering criteria allowed for the presence of modest genetic heterogeneity or missing data but also identified multiple candidate genes. However, genotypic and phenotypic stratification highlighted MLL2, which encodes a Trithorax-group histone methyltransferase: seven probands had newly identified nonsense or frameshift mutations in this gene. Follow-up Sanger sequencing detected MLL2 mutations in two of the three remaining individuals with Kabuki syndrome (cases) and in 26 of 43 additional cases. In families where parental DNA was available, the mutation was confirmed to be de novo (n = 12) or transmitted (n = 2) in concordance with phenotype. Our results strongly suggest that mutations in MLL2 are a major cause of Kabuki syndrome.
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exome sequencing identifies MLL2 mutations as a cause of kabuki syndrome
Nature Genetics, 2010Co-Authors: Sarah B Ng, Mark C Hannibal, Margaret J Mcmillin, Heidi I S Gildersleeve, Abigail W Bigham, Kati J Buckingham, Anita E. Beck, Holly K. TaborAbstract:Jay Shendure and colleagues report exome sequencing of ten individuals with Kabuki syndrome. They identify mutations in MLL2, encoding a Trithorax-group histone methyltransferase, as causal for this rare autosomal dominant malformation disorder.
Simon C Body - One of the best experts on this subject based on the ideXlab platform.
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the mbl2 lyqa secretor haplotype is an independent predictor of postoperative myocardial infarction in whites undergoing coronary artery bypass graft surgery
Circulation, 2007Co-Authors: Charles D Collard, Stanton K Shernan, Amanda A Fox, Toralf Bernig, Stephen J Chanock, William K Vaughn, Kazue Takahashi, Alan Ezekowitz, Petr Jarolim, Simon C BodyAbstract:Background— Mannose-binding lectin (MBL) is an important component of innate immunity and activator of the lectin complement pathway. Within the MBL2 gene are seven 5′ “secretor” haplotypes that code for altered serum MBL levels and complement activation. However, recent evidence suggests that 3′ MBL2 haplotypes may also modify MBL function and circulating levels. Because MBL and the lectin complement pathway have been implicated in cardiovascular injury, we investigated whether MBL2 haplotypes are independently associated with an increased risk of postoperative myocardial infarction (PMI) in patients undergoing coronary artery bypass graft surgery. Methods and Results— Genotyping of 18 polymorphic sites within the MBL2 gene was performed in a prospective, longitudinal multi-institutional study of 978 patients undergoing primary coronary artery bypass graft-only surgery with cardiopulmonary bypass between August 2001 and May 2005. After adjustment for multiple comparisons by permutation testing, multivariate, stepwise logistic regression, including a score test, was performed controlling for patient demographics, preoperative risk factors, medications, and intraoperative variables to determine if MBL2 secretor haplotypes are independent predictors of PMI in whites undergoing primary coronary artery bypass graft surgery. Neither the 5′ nor 3′ MBL2 haplotypes alone were associated with an increased incidence of PMI. However, the incidence of PMI in whites (n=843) expressing the combined MBL2 5′ LYQA secretor haplotype (CGTCGG) and 3′ haplotype (CGGGT) was significantly higher than in whites not expressing the haplotype (38% versus 10%; P <0.007). Moreover, the combined MBL2 LYQA secretor haplotype was an independent predictor of PMI in whites after primary coronary artery bypass graft surgery after adjustment for other covariates ( P <0.02; adjusted OR: 3.97; 95% CI: 1.30 to 12.07). The combined MBL2 LYQA secretor haplotype in whites was also an independent predictor of postoperative CKMB levels exceeding 60 ng/mL ( P <0.02; adjusted OR: 4.48; 95% CI: 1.95 to 16.80). Inclusion of the combined MBL2 LYQA secretor haplotype improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.715 versus 0.705). Conclusions— The combined MBL2 LYQA secretor haplotype is a novel independent predictor of PMI and may aid in preoperative risk stratification of whites undergoing primary coronary artery bypass graft surgery.
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abstract 3118 the mbl2 lyqa secretor haplotype is an independent predictor of postoperative myocardial infarction mi in caucasians undergoing coronary artery bypass graft cabg surgery
Circulation, 2006Co-Authors: Charles D Collard, Stanton K Shernan, Toralf Bernig, Stephen J Chanock, William K Vaughn, Kazue Takahashi, Alan Ezekowitz, Petr Jarolim, Amanda K Fox, Simon C BodyAbstract:Background and Aim: Mannose binding-lectin (MBL) is an important component of innate immunity, and activator of the lectin complement pathway. Within the MBL2 gene are seven “secretor” haplotypes that code for altered serum MBL levels and complement activation. As complement is important in the pathophysiology of myocardial injury, we determined if MBL2 secretor haplotypes are independently associated with an increased risk of in-hospital, postoperative MI in patients undergoing CABG surgery. Methods: Prospective, longitudinal multi-institutional study of 978 patients undergoing primary, elective CABG-only surgery with cardiopulmonary bypass between 8/2001 and 5/2005. Genotyping of 18 polymorphic sites within the MBL2 gene was performed at the National Cancer Institute using Sequenom MALDI-TOF. Multivariate, stepwise logistic regression was performed controlling for patient demographics, preoperative risk factors, medications and intraoperative variables to determine if MBL2 secretor haplotypes are independent predictors of in-hospital, postoperative MI (defined by clinician diagnosis of MI by ECG or enzyme criteria). Results: The incidence of postoperative MI in Caucasians (n = 843) expressing the MBL2 LYQA secretor haplotype (CGTCGG) on the backbone of the extended haplotype CGTCGGCGGGT was significantly higher than Caucasians not expressing the haplotype (42% vs. 10%; P MBL2 LYQA secretor haplotype was an independent predictor of postoperative MI in Caucasians following elective, primary CABG surgery after adjustment for other covariates (p MBL2 LYQA secretor haplotype in Caucasians was also an independent predictor of creatine kinase MB (CKMB) levels exceeding 60 ng/ml on postoperative day one (p MBL2 LYQA secretor haplotype in non-Caucasians (n = 135) was not independently associated with an increased risk of postoperative MI following elective, primary CABG surgery. Conclusions: The MBL2 LYQA secretor haplotype is a novel independent predictor of postoperative MI in Caucasians undergoing primary, elective CABG surgery.
Luciano Di Croce - One of the best experts on this subject based on the ideXlab platform.
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not all h3k4 methylations are created equal MLL2 compass dependency in primordial germ cell specification
Molecular Cell, 2017Co-Authors: Xin Gao, Kaixiang Cao, Marc A Morgan, Gloria Mas, Edwin R Smith, Andrew Volk, Elizabeth T Bartom, John D Crispino, Luciano Di CroceAbstract:The spatiotemporal regulation of gene expression is central for cell-lineage specification during embryonic development and is achieved through the combinatorial action of transcription factors/co-factors and epigenetic states at cis-regulatory elements. Here, we show that in addition to implementing H3K4me3 at promoters of bivalent genes, MLL2 (KMT2B)/COMPASS can also implement H3K4me3 at a subset of non-TSS regulatory elements, a subset of which shares epigenetic signatures of active enhancers. Our mechanistic studies reveal that association of MLL2's CXXC domain with CpG-rich regions plays an instrumental role for chromatin targeting and subsequent implementation of H3K4me3. Although MLL2/COMPASS is required for H3K4me3 implementation on thousands of loci, generation of catalytically mutant MLL2/COMPASS demonstrated that H3K4me3 implemented by this enzyme was essential for expression of a subset of genes, including those functioning in the control of transcriptional programs during embryonic development. Our findings suggest that not all H3K4 trimethylations implemented by MLL2/COMPASS are functionally equivalent.
Anita E. Beck - One of the best experts on this subject based on the ideXlab platform.
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spectrum of MLL2 alr mutations in 110 cases of kabuki syndrome
American Journal of Medical Genetics Part A, 2011Co-Authors: Mark C Hannibal, Jeffrey E Ming, Sarah B Ng, Margaret J Mcmillin, Heidi I S Gildersleeve, Abigail W Bigham, Kati J Buckingham, Anita E. Beck, Holly K. TaborAbstract:Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.
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exome sequencing identifies MLL2 mutations as a cause of kabuki syndrome
Nature Genetics, 2010Co-Authors: Abigail W Bigham, Mark C Hannibal, Margaret J Mcmillin, Heidi I S Gildersleeve, Kati J Buckingham, Anita E. Beck, Holly K. TaborAbstract:We demonstrate the successful application of exome sequencing to discover a gene for an autosomal dominant disorder, Kabuki syndrome (OMIM%147920). We subjected the exomes of ten unrelated probands to massively parallel sequencing. After filtering against existing SNP databases, there was no compelling candidate gene containing previously unknown variants in all affected individuals. Less stringent filtering criteria allowed for the presence of modest genetic heterogeneity or missing data but also identified multiple candidate genes. However, genotypic and phenotypic stratification highlighted MLL2, which encodes a Trithorax-group histone methyltransferase: seven probands had newly identified nonsense or frameshift mutations in this gene. Follow-up Sanger sequencing detected MLL2 mutations in two of the three remaining individuals with Kabuki syndrome (cases) and in 26 of 43 additional cases. In families where parental DNA was available, the mutation was confirmed to be de novo (n = 12) or transmitted (n = 2) in concordance with phenotype. Our results strongly suggest that mutations in MLL2 are a major cause of Kabuki syndrome.
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exome sequencing identifies MLL2 mutations as a cause of kabuki syndrome
Nature Genetics, 2010Co-Authors: Sarah B Ng, Mark C Hannibal, Margaret J Mcmillin, Heidi I S Gildersleeve, Abigail W Bigham, Kati J Buckingham, Anita E. Beck, Holly K. TaborAbstract:Jay Shendure and colleagues report exome sequencing of ten individuals with Kabuki syndrome. They identify mutations in MLL2, encoding a Trithorax-group histone methyltransferase, as causal for this rare autosomal dominant malformation disorder.