Identifying the genetic basis of variably protease-sensitive prionopathy (VPSPr)
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PROVIDER: PRJNA1246681 | ENA |
REPOSITORIES: ENA
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Project description:Identifying the genetic basis of variably protease-sensitive prionopathy (VPSPr)
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Project description:The bacterial CRISPR-Cas9 (Cas9) nuclease has become a powerful genome manipulation tool for a wide range of organisms 1-3. However, it has yet to fully leverage the pervasive presence of DNA methylation in genomes4-10. To fill this gap, we report biochemical, structural, and human genome editing characterizations of a methylation-sensitive Cas9 (ThermoCas9). ThermoCas9 efficiently binds and cleaves DNA upstream of its protospacer adjacent motif (PAM) 5´-NNNNCGA-3´ or 5´-NNNNCCA-3´ in vitro. Methylation of the fifth cytosine in either PAM sequence (5mCpG or 5mCpC), however, significantly inhibits ThermoCas9 activity. Cryogenic electron microscopy structures of ThermoCas9 in pre- and post-cleavage states at 2.8 Å and 2.2 Å resolution, respectively, reveal the molecular basis for the stringent requirement of the unmethylated cytosine in PAM binding and provides guidance for further enzyme engineering. We demonstrated methylation-sensitive editing by ThermoCas9 in human cell lines with distinct DNA methylation landscapes. Moreover, we demonstrated that a catalytically enhanced ThermoCas9 efficiently targets luminal expression signature genes that are consistently hypomethylated in breast cancer patients. Due to its sensitivity to DNA methylation, ThermoCas9 can target cells specifically with disease-related hypomethylation which adds another layer of precision to genome editing technologies.
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Project description:Sinorhizobium meliloti establishes symbiotic relationship with compatible leguminous plants by inducing root nodule formation, colonizing such nodules, and fixing molecular nitrogen for the host in exchange for carbon compounds. This mutualistic process requires complex communication and tight regulation to allow yet constrain infection to specific tissues. Production of succinoglycan, or exopolysaccharide-I (EPS-I), enables S. meliloti to invade the root cortex via infection threads. A previous genetic screen identified jspA (SMc03872), encoding an extracytoplasmic protease, as a regulator of EPS-I production. To elucidate its molecular role, we performed transcriptome analyses of strains overexpressing wild-type or mutant alleles of jspA. We observed changes in gene expression suggesting that JspA contributes to symbiosis efficiency by modulating the critical ExoR-ExoS-ChvI signaling pathway.
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Project description:The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), characterized by aneuploidy and poor outcome, is unknown. Here, using complementary genome-wide profiling approaches, we show that hypodiploid ALL comprises two major subtypes that differ in the severity of aneuploidy, transcriptional profile and submicroscopic genetic alterations. Near haploid cases with 24-31 chromosomes frequently harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and IKZF3 (AIOLOS; 13%). In contrast, low hypodiploid ALL cases with 32-39 chromosomes are characterized by TP53 alterations (88%), almost half of which are present in non-tumor cells, and have alterations of IKZF2 (HELIOS; 53%) and RB1 (41%). Both near haploid and low hypodiploid tumors exhibit activation of Ras and PI3K signaling pathways, and are sensitive to PI3K inhibition, indicating that these drugs should be explored as a new therapeutic strategy for this frequently lethal form of leukemia. Gene expression profiling was performed on 117 single diagnosis tumor samples and one relapse sample [SJHYPO117]. No control or reference samples were included.
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Project description:Protease Encoding bacteria in arable fields
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Project description:The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), characterized by aneuploidy and poor outcome, is unknown. Here, using complementary genome-wide profiling approaches, we show that hypodiploid ALL comprises two major subtypes that differ in the severity of aneuploidy, transcriptional profile and submicroscopic genetic alterations. Near haploid cases with 24-31 chromosomes frequently harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and IKZF3 (AIOLOS; 13%). In contrast, low hypodiploid ALL cases with 32-39 chromosomes are characterized by TP53 alterations (88%), almost half of which are present in non-tumor cells, and have alterations of IKZF2 (HELIOS; 53%) and RB1 (41%). Both near haploid and low hypodiploid tumors exhibit activation of Ras and PI3K signaling pathways, and are sensitive to PI3K inhibition, indicating that these drugs should be explored as a new therapeutic strategy for this frequently lethal form of leukemia.
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