Albert Jeltsch | University of Stuttgart (original) (raw)
Papers by Albert Jeltsch
Springer eBooks, 2022
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Journal of Biological Chemistry, Oct 1, 2022
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EMBO Reports, Apr 1, 2001
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FEBS Journal, May 1, 2021
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Journal of Biotechnology, Apr 1, 2015
Hydrogen (H2) is a potential alternative energy carrier which only produces water and heat upon c... more Hydrogen (H2) is a potential alternative energy carrier which only produces water and heat upon combustion. Today, industrial hydrogen production mainly uses thermochemical processes based on fossil fuels or electrolysis of water. Therefore, biotechnological approaches to produce H2 from biomass are an interesting alternative. We introduce here a novel direct hydrogen measurement system using a semiconducting device specific for hydrogen detection. Using this device, a bacterium producing considerable amounts of hydrogen under aerobic cultivation was isolated and identified by 16S ribosomal DNA sequencing as Citrobacter sp. The enzyme responsible for the observed hydrogenase activity was partially purified by 3 chromatographic purification steps and could be identified by peptide mass fingerprinting to be a type 2 [NiFe]-hydrogenase. Expression of the [NiFe]-hydrogenase 2 containing operon from Citrobacter sp. SG in Escherichia coli allowed recombinant hydrogen production. The [NiFe]-hydrogenase 2 identified here may be useful for biotechnological hydrogen production. We speculate that the expression of the hydrogenase in Citrobacter may be an adaptation to growth in acidic conditions.
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Journal of Molecular Biology, Aug 8, 2003
ABSTRACT We have determined the crystal structure of the PvuII endonuclease in the presence of Mg... more ABSTRACT We have determined the crystal structure of the PvuII endonuclease in the presence of Mg(2+). According to the structural data, divalent metal ion binding in the PvuII subunits is highly asymmetric. The PvuII-Mg(2+) complex has two distinct metal ion binding sites, one in each monomer. One site is formed by the catalytic residues Asp58 and Glu68, and has extensive similarities to a catalytically important site found in all structurally examined restriction endonucleases. The other binding site is located in the other monomer, in the immediate vicinity of the hydroxyl group of Tyr94; it has no analogy to metal ion binding sites found so far in restriction endonucleases. To assign the number of metal ions involved and to better understand the role of Mg(2+) binding to Tyr94 for the function of PvuII, we have exchanged Tyr94 by Phe and characterized the metal ion dependence of DNA cleavage of wild-type PvuII and the Y94F variant. Wild-type PvuII cleaves both strands of the DNA in a concerted reaction. Mg(2+) binding, as measured by the Mg(2+) dependence of DNA cleavage, occurs with a Hill coefficient of 4, meaning that at least two metal ions are bound to each subunit in a cooperative fashion upon formation of the active complex. Quenched-flow experiments show that DNA cleavage occurs about tenfold faster if Mg(2+) is pre-incubated with enzyme or DNA than if preformed enzyme-DNA complexes are mixed with Mg(2+). These results show that Mg(2+) cannot easily enter the active center of the preformed enzyme-DNA complex, but that for fast cleavage the metal ions must already be bound to the apoenzyme and carried with the enzyme into the enzyme-DNA complex. The Y94F variant, in contrast to wild-type PvuII, does not cleave DNA in a concerted manner and metal ion binding occurs with a Hill coefficient of 1. These results indicate that removal of the Mg(2+) binding site at Tyr94 completely disrupts the cooperativity in DNA cleavage. Moreover, in quenched-flow experiments Y94F cleaves DNA about ten times more slowly than wild-type PvuII, regardless of the order of mixing. From these results we conclude that wild-type PvuII cleaves DNA in a fast and concerted reaction, because the Mg(2+) required for catalysis are already bound at the enzyme, one of them at Tyr94. We suggest that this Mg(2+) is shifted to the active center during binding of a specific DNA substrate. These results, for the first time, shed light on the pathway by which metal ions as essential cofactors enter the catalytic center of restriction endonucleases.
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FEBS Letters, May 25, 2012
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Background Epigenome editing refers to the targeted reprogramming of genomic loci using an EpiEdi... more Background Epigenome editing refers to the targeted reprogramming of genomic loci using an EpiEditor which may consist of dCas9, DNMT3A/3L and sgRNA. Methylation of the locus can lead to a modulation of gene expression. Allele-specific DNA methylation (ASM) refers to the targeted methylation delivery only to one allele of a locus. In the context of diseases caused by a dominant mutation, the selective DNA methylation of the mutant allele could be used to repress its expression but retain the functionality of the normal gene. Results To set up allele-specific targeted DNA methylation, target regions were selected from hypomethylated CGIs bearing a SNP in their promoters in the HEK293 cell line. We aimed at delivering maximum DNA methylation with highest allelic specificity in the targeted regions. Placing SNPs in the PAM or seed regions of the sgRNA, we designed 24 different sgRNAs targeting single alleles. We achieved efficient ASM in multiple cases, such as ISG15, MSH6, GPD1L, MRPL...
Bookmarks Related papers MentionsView impact
Protein Science
The DNMT3A DNA methyltransferase and MECP2 methylation reader are highly expressed in neurons. Bo... more The DNMT3A DNA methyltransferase and MECP2 methylation reader are highly expressed in neurons. Both proteins interact via their DNMT3A‐ADD and MECP2‐TRD domains, and the MECP2 interaction regulates the activity and subnuclear localization of DNMT3A. Here, we mapped the interface of both domains using peptide SPOT array binding, protein pull‐down, equilibrium peptide binding assays, and structural analyses. The region D529‐D531 on the surface of the ADD domain was identified as interaction point with the TRD domain. This includes important residues of the histone H3 N‐terminal tail binding site to the ADD domain, explaining why TRD and H3 binding to the ADD domain is competitive. On the TRD domain, residues 214–228 containing K219 and K223 were found to be essential for the ADD interaction. This part represents a folded patch within the otherwise largely disordered TRD domain. A crystal structure analysis of ADD revealed that the identified H3/TDR lysine binding pocket is occupied by...
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Biochimie
The H3.3 G34W mutation has been observed in 90% of the patients affected by giant cell tumor of b... more The H3.3 G34W mutation has been observed in 90% of the patients affected by giant cell tumor of bone (GCTB). It had been shown to reduce the activity of the SETD2 H3K36 protein lysine methyltransferase (PKMT) and lead to genome wide changes in epigenome modifications including a global reduction in DNA methylation. Here, we investigated the effect of the H3.3 G34W mutation on the activity of the H3K36me2 methyltransferase NSD1, because NSD1 is known to play an important role in the differentiation of chondrocytes and osteoblasts. Unexpectedly, we observed that H3.3 G34W has a gain-of-function effect and it stimulates K36 methylation by NSD1 by about 2.3-fold with peptide substrates and 6.3-fold with recombinant nucleosomal substrates. This effect is specific for NSD1, as NSD2 and SETD2 show only a very mild stimulation and even reduced activity on G34W substrates. The potential downstream effects of the G34W induced hyperactivity of NSD1 on DNA methylation, H3K27me3, histone acetylation and splicing are discussed.
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ACS Chemical Biology
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European Neuropsychopharmacology, 2017
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Molecular Psychiatry, 2021
Recent evidence has documented the potential roles of histone-modifying enzymes in autism-spectru... more Recent evidence has documented the potential roles of histone-modifying enzymes in autism-spectrum disorder (ASD). Aberrant histone H3 lysine 9 (H3K9) dimethylation resulting from genetic variants in histone methyltransferases is known for neurodevelopmental and behavioral anomalies. However, a systematic examination of H3K9 methylation dynamics in ASD is lacking. Here we resequenced nine genes for histone methyltransferases and demethylases involved in H3K9 methylation in individuals with ASD and healthy controls using targeted next-generation sequencing. We identified a novel rare variant (A211S) in the SUV39H2, which was predicted to be deleterious. The variant showed strongly reduced histone methyltransferase activity in vitro. In silico analysis showed that the variant destabilizes the hydrophobic core and allosterically affects the enzyme activity. The Suv39h2-KO mice displayed hyperactivity and reduced behavioral flexibility in learning the tasks that required complex behavioral adaptation, which is relevant for ASD. The Suv39h2 deficit evoked an elevated expression of a subset of protocadherin β (Pcdhb) cluster genes in the embryonic brain, which is attributable to the loss of H3K9 trimethylation (me3) at the gene promoters. Reduced H3K9me3 persisted in the cerebellum of Suv39h2-deficient mice to an adult stage. Congruently, reduced expression of SUV39H1 and SUV39H2 in the postmortem brain samples of ASD individuals was observed, underscoring the role of H3K9me3 deficiency in ASD etiology. The present study provides direct evidence for the role of SUV39H2 in ASD and suggests a molecular cascade of SUV39H2 dysfunction leading to H3K9me3 deficiency followed by an untimely, elevated expression of Pcdhb cluster genes during early neurodevelopment.
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Nucleic Acids Research, 2021
The lysine specific demethylase 1 (LSD1) plays a pivotal role in cellular differentiation by regu... more The lysine specific demethylase 1 (LSD1) plays a pivotal role in cellular differentiation by regulating the expression of key developmental genes in concert with different coregulatory proteins. This process is impaired in different cancer types and incompletely understood. To comprehensively identify functional coregulators of LSD1, we established a novel tractable fluorescent reporter system to monitor LSD1 activity in living cells. Combining this reporter system with a state-of-the-art multiplexed RNAi screen, we identify the DEAD-box helicase 19A (DDX19A) as a novel coregulator and demonstrate that suppression of Ddx19a results in an increase of R-loops and reduced LSD1-mediated gene silencing. We further show that DDX19A binds to tri-methylated lysine 27 of histone 3 (H3K27me3) and it regulates gene expression through the removal of transcription promoting R-loops. Our results uncover a novel transcriptional regulatory cascade where the downregulation of genes is dependent on t...
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Cell Death Regulation in Health and Disease - Part A, 2020
The cytokine tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of... more The cytokine tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the large TNF superfamily that can trigger apoptosis in transformed or infected cells by binding and activating two receptors, TRAIL receptor 1 (TRAILR1) and TRAIL receptor 2 (TRAILR2). Compared to other death ligands of the same family, TRAIL induces apoptosis preferentially in malignant cells while sparing normal tissue and has therefore been extensively investigated for its suitability as an anti-cancer agent. Recently, it was noticed that TRAIL receptor signaling is also linked to endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The role of TRAIL receptors in regulating cellular apoptosis susceptibility therefore is broader than previously thought. Here, we provide an overview of TRAIL-induced signaling, covering the core signal transduction during extrinsic apoptosis as well as its link to alternative outcomes, such as necroptosis or NF-κB activation. We discuss how environmental factors, transcriptional regulators, and genetic or epigenetic alterations regulate TRAIL receptors and thus alter cellular TRAIL susceptibility. Finally, we provide insight into the role of TRAIL receptors in signaling scenarios that engage the unfolded protein response and discuss how these findings might be translated into new combination therapies for cancer treatment.
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Bookmarks Related papers MentionsView impact
Journal of Molecular Biology, 2019
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Journal of Molecular Biology, 2019
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Journal of Molecular Biology, 2019
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Oncogene, 2019
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Springer eBooks, 2022
Bookmarks Related papers MentionsView impact
Journal of Biological Chemistry, Oct 1, 2022
Bookmarks Related papers MentionsView impact
EMBO Reports, Apr 1, 2001
Bookmarks Related papers MentionsView impact
FEBS Journal, May 1, 2021
Bookmarks Related papers MentionsView impact
Journal of Biotechnology, Apr 1, 2015
Hydrogen (H2) is a potential alternative energy carrier which only produces water and heat upon c... more Hydrogen (H2) is a potential alternative energy carrier which only produces water and heat upon combustion. Today, industrial hydrogen production mainly uses thermochemical processes based on fossil fuels or electrolysis of water. Therefore, biotechnological approaches to produce H2 from biomass are an interesting alternative. We introduce here a novel direct hydrogen measurement system using a semiconducting device specific for hydrogen detection. Using this device, a bacterium producing considerable amounts of hydrogen under aerobic cultivation was isolated and identified by 16S ribosomal DNA sequencing as Citrobacter sp. The enzyme responsible for the observed hydrogenase activity was partially purified by 3 chromatographic purification steps and could be identified by peptide mass fingerprinting to be a type 2 [NiFe]-hydrogenase. Expression of the [NiFe]-hydrogenase 2 containing operon from Citrobacter sp. SG in Escherichia coli allowed recombinant hydrogen production. The [NiFe]-hydrogenase 2 identified here may be useful for biotechnological hydrogen production. We speculate that the expression of the hydrogenase in Citrobacter may be an adaptation to growth in acidic conditions.
Bookmarks Related papers MentionsView impact
Journal of Molecular Biology, Aug 8, 2003
ABSTRACT We have determined the crystal structure of the PvuII endonuclease in the presence of Mg... more ABSTRACT We have determined the crystal structure of the PvuII endonuclease in the presence of Mg(2+). According to the structural data, divalent metal ion binding in the PvuII subunits is highly asymmetric. The PvuII-Mg(2+) complex has two distinct metal ion binding sites, one in each monomer. One site is formed by the catalytic residues Asp58 and Glu68, and has extensive similarities to a catalytically important site found in all structurally examined restriction endonucleases. The other binding site is located in the other monomer, in the immediate vicinity of the hydroxyl group of Tyr94; it has no analogy to metal ion binding sites found so far in restriction endonucleases. To assign the number of metal ions involved and to better understand the role of Mg(2+) binding to Tyr94 for the function of PvuII, we have exchanged Tyr94 by Phe and characterized the metal ion dependence of DNA cleavage of wild-type PvuII and the Y94F variant. Wild-type PvuII cleaves both strands of the DNA in a concerted reaction. Mg(2+) binding, as measured by the Mg(2+) dependence of DNA cleavage, occurs with a Hill coefficient of 4, meaning that at least two metal ions are bound to each subunit in a cooperative fashion upon formation of the active complex. Quenched-flow experiments show that DNA cleavage occurs about tenfold faster if Mg(2+) is pre-incubated with enzyme or DNA than if preformed enzyme-DNA complexes are mixed with Mg(2+). These results show that Mg(2+) cannot easily enter the active center of the preformed enzyme-DNA complex, but that for fast cleavage the metal ions must already be bound to the apoenzyme and carried with the enzyme into the enzyme-DNA complex. The Y94F variant, in contrast to wild-type PvuII, does not cleave DNA in a concerted manner and metal ion binding occurs with a Hill coefficient of 1. These results indicate that removal of the Mg(2+) binding site at Tyr94 completely disrupts the cooperativity in DNA cleavage. Moreover, in quenched-flow experiments Y94F cleaves DNA about ten times more slowly than wild-type PvuII, regardless of the order of mixing. From these results we conclude that wild-type PvuII cleaves DNA in a fast and concerted reaction, because the Mg(2+) required for catalysis are already bound at the enzyme, one of them at Tyr94. We suggest that this Mg(2+) is shifted to the active center during binding of a specific DNA substrate. These results, for the first time, shed light on the pathway by which metal ions as essential cofactors enter the catalytic center of restriction endonucleases.
Bookmarks Related papers MentionsView impact
FEBS Letters, May 25, 2012
Bookmarks Related papers MentionsView impact
Background Epigenome editing refers to the targeted reprogramming of genomic loci using an EpiEdi... more Background Epigenome editing refers to the targeted reprogramming of genomic loci using an EpiEditor which may consist of dCas9, DNMT3A/3L and sgRNA. Methylation of the locus can lead to a modulation of gene expression. Allele-specific DNA methylation (ASM) refers to the targeted methylation delivery only to one allele of a locus. In the context of diseases caused by a dominant mutation, the selective DNA methylation of the mutant allele could be used to repress its expression but retain the functionality of the normal gene. Results To set up allele-specific targeted DNA methylation, target regions were selected from hypomethylated CGIs bearing a SNP in their promoters in the HEK293 cell line. We aimed at delivering maximum DNA methylation with highest allelic specificity in the targeted regions. Placing SNPs in the PAM or seed regions of the sgRNA, we designed 24 different sgRNAs targeting single alleles. We achieved efficient ASM in multiple cases, such as ISG15, MSH6, GPD1L, MRPL...
Bookmarks Related papers MentionsView impact
Protein Science
The DNMT3A DNA methyltransferase and MECP2 methylation reader are highly expressed in neurons. Bo... more The DNMT3A DNA methyltransferase and MECP2 methylation reader are highly expressed in neurons. Both proteins interact via their DNMT3A‐ADD and MECP2‐TRD domains, and the MECP2 interaction regulates the activity and subnuclear localization of DNMT3A. Here, we mapped the interface of both domains using peptide SPOT array binding, protein pull‐down, equilibrium peptide binding assays, and structural analyses. The region D529‐D531 on the surface of the ADD domain was identified as interaction point with the TRD domain. This includes important residues of the histone H3 N‐terminal tail binding site to the ADD domain, explaining why TRD and H3 binding to the ADD domain is competitive. On the TRD domain, residues 214–228 containing K219 and K223 were found to be essential for the ADD interaction. This part represents a folded patch within the otherwise largely disordered TRD domain. A crystal structure analysis of ADD revealed that the identified H3/TDR lysine binding pocket is occupied by...
Bookmarks Related papers MentionsView impact
Biochimie
The H3.3 G34W mutation has been observed in 90% of the patients affected by giant cell tumor of b... more The H3.3 G34W mutation has been observed in 90% of the patients affected by giant cell tumor of bone (GCTB). It had been shown to reduce the activity of the SETD2 H3K36 protein lysine methyltransferase (PKMT) and lead to genome wide changes in epigenome modifications including a global reduction in DNA methylation. Here, we investigated the effect of the H3.3 G34W mutation on the activity of the H3K36me2 methyltransferase NSD1, because NSD1 is known to play an important role in the differentiation of chondrocytes and osteoblasts. Unexpectedly, we observed that H3.3 G34W has a gain-of-function effect and it stimulates K36 methylation by NSD1 by about 2.3-fold with peptide substrates and 6.3-fold with recombinant nucleosomal substrates. This effect is specific for NSD1, as NSD2 and SETD2 show only a very mild stimulation and even reduced activity on G34W substrates. The potential downstream effects of the G34W induced hyperactivity of NSD1 on DNA methylation, H3K27me3, histone acetylation and splicing are discussed.
Bookmarks Related papers MentionsView impact
ACS Chemical Biology
Bookmarks Related papers MentionsView impact
European Neuropsychopharmacology, 2017
Bookmarks Related papers MentionsView impact
Molecular Psychiatry, 2021
Recent evidence has documented the potential roles of histone-modifying enzymes in autism-spectru... more Recent evidence has documented the potential roles of histone-modifying enzymes in autism-spectrum disorder (ASD). Aberrant histone H3 lysine 9 (H3K9) dimethylation resulting from genetic variants in histone methyltransferases is known for neurodevelopmental and behavioral anomalies. However, a systematic examination of H3K9 methylation dynamics in ASD is lacking. Here we resequenced nine genes for histone methyltransferases and demethylases involved in H3K9 methylation in individuals with ASD and healthy controls using targeted next-generation sequencing. We identified a novel rare variant (A211S) in the SUV39H2, which was predicted to be deleterious. The variant showed strongly reduced histone methyltransferase activity in vitro. In silico analysis showed that the variant destabilizes the hydrophobic core and allosterically affects the enzyme activity. The Suv39h2-KO mice displayed hyperactivity and reduced behavioral flexibility in learning the tasks that required complex behavioral adaptation, which is relevant for ASD. The Suv39h2 deficit evoked an elevated expression of a subset of protocadherin β (Pcdhb) cluster genes in the embryonic brain, which is attributable to the loss of H3K9 trimethylation (me3) at the gene promoters. Reduced H3K9me3 persisted in the cerebellum of Suv39h2-deficient mice to an adult stage. Congruently, reduced expression of SUV39H1 and SUV39H2 in the postmortem brain samples of ASD individuals was observed, underscoring the role of H3K9me3 deficiency in ASD etiology. The present study provides direct evidence for the role of SUV39H2 in ASD and suggests a molecular cascade of SUV39H2 dysfunction leading to H3K9me3 deficiency followed by an untimely, elevated expression of Pcdhb cluster genes during early neurodevelopment.
Bookmarks Related papers MentionsView impact
Nucleic Acids Research, 2021
The lysine specific demethylase 1 (LSD1) plays a pivotal role in cellular differentiation by regu... more The lysine specific demethylase 1 (LSD1) plays a pivotal role in cellular differentiation by regulating the expression of key developmental genes in concert with different coregulatory proteins. This process is impaired in different cancer types and incompletely understood. To comprehensively identify functional coregulators of LSD1, we established a novel tractable fluorescent reporter system to monitor LSD1 activity in living cells. Combining this reporter system with a state-of-the-art multiplexed RNAi screen, we identify the DEAD-box helicase 19A (DDX19A) as a novel coregulator and demonstrate that suppression of Ddx19a results in an increase of R-loops and reduced LSD1-mediated gene silencing. We further show that DDX19A binds to tri-methylated lysine 27 of histone 3 (H3K27me3) and it regulates gene expression through the removal of transcription promoting R-loops. Our results uncover a novel transcriptional regulatory cascade where the downregulation of genes is dependent on t...
Bookmarks Related papers MentionsView impact
Cell Death Regulation in Health and Disease - Part A, 2020
The cytokine tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of... more The cytokine tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the large TNF superfamily that can trigger apoptosis in transformed or infected cells by binding and activating two receptors, TRAIL receptor 1 (TRAILR1) and TRAIL receptor 2 (TRAILR2). Compared to other death ligands of the same family, TRAIL induces apoptosis preferentially in malignant cells while sparing normal tissue and has therefore been extensively investigated for its suitability as an anti-cancer agent. Recently, it was noticed that TRAIL receptor signaling is also linked to endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The role of TRAIL receptors in regulating cellular apoptosis susceptibility therefore is broader than previously thought. Here, we provide an overview of TRAIL-induced signaling, covering the core signal transduction during extrinsic apoptosis as well as its link to alternative outcomes, such as necroptosis or NF-κB activation. We discuss how environmental factors, transcriptional regulators, and genetic or epigenetic alterations regulate TRAIL receptors and thus alter cellular TRAIL susceptibility. Finally, we provide insight into the role of TRAIL receptors in signaling scenarios that engage the unfolded protein response and discuss how these findings might be translated into new combination therapies for cancer treatment.
Bookmarks Related papers MentionsView impact
Bookmarks Related papers MentionsView impact
Journal of Molecular Biology, 2019
Bookmarks Related papers MentionsView impact
Journal of Molecular Biology, 2019
Bookmarks Related papers MentionsView impact
Journal of Molecular Biology, 2019
Bookmarks Related papers MentionsView impact
Oncogene, 2019
Bookmarks Related papers MentionsView impact