32 research outputs found
Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence.
To determine the role for mutations of MECP2 in Rett syndrome, we generated isogenic lines of human induced pluripotent stem cells, neural progenitor cells, and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal-specific gene expression changes, including induction of a senescence-associated secretory phenotype (SASP) program. Patient-derived neurons made without MECP2 showed signs of stress, including induction of P53, and senescence. The induction of P53 appeared to affect dendritic branching in Rett neurons, as P53 inhibition restored dendritic complexity. The induction of P53 targets was also detectable in analyses of human Rett patient brain, suggesting that this disease-in-a-dish model can provide relevant insights into the human disorder
Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA
Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA
Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1-STAT4 region
IntroductionRecent studies identified STAT4 (signal transducers and activators of transcription-4) as a susceptibility gene for systemic lupus erythematosus (SLE). STAT1 is encoded adjacently to STAT4 on 2q32.2-q32.3, upregulated in peripheral blood mononuclear cells from SLE patients, and functionally relevant to SLE. This study was conducted to test whether STAT4 is associated with SLE in a Japanese population also, to identify the risk haplotype, and to examine the potential genetic contribution of STAT1. To accomplish these aims, we carried out a comprehensive association analysis of 52 tag single nucleotide polymorphisms (SNPs) encompassing the STAT1-STAT4 region.MethodsIn the first screening, 52 tag SNPs were selected based on HapMap Phase II JPT (Japanese in Tokyo, Japan) data, and case-control association analysis was carried out on 105 Japanese female patients with SLE and 102 female controls. For associated SNPs, additional cases and controls were genotyped and association was analyzed using 308 SLE patients and 306 controls. Estimation of haplotype frequencies and an association study using the permutation test were performed with Haploview version 4.0 software. Population attributable risk percentage was estimated to compare the epidemiological significance of the risk genotype among populations.ResultsIn the first screening, rs7574865, rs11889341, and rs10168266 in STAT4 were most significantly associated (P < 0.01). Significant association was not observed for STAT1. Subsequent association studies of the three SNPs using 308 SLE patients and 306 controls confirmed a strong association of the rs7574865T allele (SLE patients: 46.3%, controls: 33.5%, P = 4.9 × 10-6, odds ratio 1.71) as well as TTT haplotype (rs10168266/rs11889341/rs7574865) (P = 1.5 × 10-6). The association was stronger in subgroups of SLE with nephritis and anti-double-stranded DNA antibodies. Population attributable risk percentage was estimated to be higher in the Japanese population (40.2%) than in Americans of European descent (19.5%).ConclusionsThe same STAT4 risk allele is associated with SLE in Caucasian and Japanese populations. Evidence for a role of STAT1 in genetic susceptibility to SLE was not detected. The contribution of STAT4 for the genetic background of SLE may be greater in the Japanese population than in Americans of European descent
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Modeling Rett Syndrome with Human Induced Pluripotent Stem Cells
Rett syndrome is a neurodevelopmental disorder that predominately affects females and is one of the most common causes of intellectual disability in females. The syndrome is characterized by developmental stagnation, cognitive deficits, seizures and other autism-like symptoms. In more than 95% of cases, Rett syndrome results from de novo mutations in the gene encoding methyl CpG binding protein 2 (MECP2), which is found on the X chromosome. However, despite numerous studies implicating the loss of this protein in Rett syndrome disease pathology, the precise reason why loss of MECP2 expression causes these clinical symptoms remains unclear. To further determine the role for mutations of MECP2 in Rett syndrome, we have generated isogenic lines of human induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs), and neurons from patient fibroblasts that either express or lack MECP2 to minimize genetic variability. Our data showed the neurons derived from NPCs adopted typical morphologies regardless of MECP2 expression, and all NPCs produced neurons and glia at the same rate. In patient iPSC-derived neurons, loss of MECP2 was correlated with Akt deactivation and reduced dendritic complexity. Molecular profiling uncovered a reduction of 5hmC, increased expression of subtelomeric genes, and shortening of telomeres in the absence of MECP2 in hiPSCs, NPCs, and neurons. Neurons made without MECP2 show signs of stress, including induction of gamma-H2aX, p53, and senescence, which are typical molecular responses to telomere shortening. The induction of p53 appeared to affect dendritic branching in Rett neurons, as p53 inhibition restored dendritic complexity. Examination of Rett patient brains uncovered similar molecular phenotypes suggesting that our disease-in-a-dish model yielded insights into authentic human Rett syndrome patient phenotypes. These data point towards a role for MECP2 in regulating telomeres and could form a molecular basis for a new understanding of the etiology of Rett syndrome
Analysis of Distal Compound Muscle Action Potential Duration in Hereditary Transthyretin Amyloidosis with Polyneuropathy
Background : Hereditary transthyretin (ATTRv) amyloidosis, a disorder accompanied by axonal polyneuropathy, is often misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). Prolongation of distally evoked compound muscle action potential duration (DCMAPD), an electrophysiological parameter of heterogeneous conduction delay at the distal part of the motor nerve suggesting demyelinating neuropathies, is included in an index of diagnostic criteria for CIDP. However, DCMAPDs are strongly influenced by low-frequency filtering (LFF) settings, which differ across hospitals worldwide. Aim : To analyze DCMAPD in patients with ATTRv amyloidosis with polyneuropathy (ATTRv-PN). Methods : DCMAPs of the median, ulnar, tibial, and peroneal nerves were recorded under LFF settings of 2, 10, and 20 Hz in 50 patients with ATTRv-PN. The changes of DCMAPD accompanied with the changes of LFF settings were analyzed. The appropriateness of the cut-off values of the DCMAPD in the latest criteria for CIDP, which defined under various LFF settings, was also validated in ATTRv-PN patients. Results : The DCMAPD was shorter with increasing LFF settings. Less than 10 % of patients with ATTRv-PN demonstrated prolonged DCMAPD of the ulnar, tibial, and peroneal nerves. In contrast, ten patients demonstrated prolonged DCMAPD in the median nerve under LFF settings of 2, 10, and/or 20 Hz. Nine of the ten cases were complicated with carpal tunnel syndrome (CTS). Conclusion : Prolongation of DCMAPDs in the ulnar, tibial, and peroneal nerves is rare in ATTRv-PN patients. DCMAPD analysis of the median nerve in patients with ATTRv-PN requires caution, because they frequently develop CTS and those with CTS may demonstrate prolonged DCMAPD.Article信州医学雑誌 72(2) : 87-94, (2024)journal articl