The sinus node (SN) is located at the apex of the cardiac conduction system, and SN dysfunction (... more The sinus node (SN) is located at the apex of the cardiac conduction system, and SN dysfunction (SND)—characterized by electrical remodeling—is generally attributed to idiopathic fibrosis or ischemic injuries in the SN. SND is associated with increased risk of cardiovascular disorders, including syncope, heart failure, and atrial arrhythmias, particularly atrial fibrillation. One of the histological SND hallmarks is degenerative atrial remodeling that is associated with conduction abnormalities and increased right atrial refractoriness. Although SND is frequently accompanied by increased fibrosis in the right atrium (RA), its molecular basis still remains elusive. Therefore, we investigated whether SND can induce significant molecular changes that account for the structural remodeling of RA. Towards this, we employed a rabbit model of experimental SND, and then compared the genome-wide RNA expression profiles in RA between SND-induced rabbits and sham-operated controls to identify t...
SARS-CoV-2 is an RNA virus whose success as a pathogen relies on its abilities to repurpose host ... more SARS-CoV-2 is an RNA virus whose success as a pathogen relies on its abilities to repurpose host RNA-binding proteins (RBPs) and to evade antiviral RBPs. To uncover the SARS-CoV-2 RNA interactome, we here develop a robust ribonucleoprotein (RNP) capture protocol and identify 109 host factors that directly bind to SARS-CoV-2 RNAs. Applying RNP capture on another coronavirus HCoV-OC43 revealed evolutionarily conserved interactions between coronaviral RNAs and host proteins. Transcriptome analyses and knockdown experiments delineated 17 antiviral RBPs including ZC3HAV1, TRIM25, PARP12, and SHFL and 8 proviral RBPs such as EIF3D and CSDE1 which are responsible for co-opting multiple steps of the mRNA life cycle. This also led to the identification of LARP1, a downstream target of the mTOR signaling pathway, as an antiviral host factor that interacts with the SARS-CoV-2 RNAs. Overall, this study provides a comprehensive list of RBPs regulating coronaviral replication and opens new avenues for therapeutic interventions
Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of ... more Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of c-MYC have the worst clinical prognosis, with only a minority of patients surviving. To address this unmet clinical need, we generated a human neural stem cell model of medulloblastoma that recapitulated the most aggressive subtype phenotypically and by mRNA expression profiling. An in silico analysis of these cells identified mTOR inhibitors as potential therapeutic agents. We hypothesized that the orally bioavailable TORC1/2 kinase inhibitor TAK228 would have activity against MYC-driven medulloblastoma. TAK228 inhibited mTORC1/2, decreased cell growth and caused apoptosis in high-MYC medulloblastoma cell lines. Comprehensive metabolic profiling of medulloblastoma orthotopic xenografts showed upregulation of glutathione compared to matched normal brain. TAK228 suppressed glutathione production. Because glutathione is required to detoxify platinum-containing chemotherapy, we hypothesized that TAK228 would cooperate with carboplatin in medulloblastoma. TAK228 synergized with carboplatin to inhibit cell growth and induce apoptosis and extended survival in orthotopic xenografts of high-MYC medulloblastoma. Brain-penetrant TORC1/2 inhibitors and carboplatin may be an effective combination therapy for high-risk medulloblastoma.
Diffuse Intrinsic Pontine Gliomas (DIPGs) are universally fatal tumors, resistant to the cytotoxi... more Diffuse Intrinsic Pontine Gliomas (DIPGs) are universally fatal tumors, resistant to the cytotoxic effects of all known therapies. We aim to better understand the mechanisms contributing to this resistance to design new combination therapies that will improve DIPG survival. DIPG's aggressive phenotype is driven by the H3K27M oncohistone mutation that leads to global genomic DNA hypomethylation and abnormal gene expression. To identify patterns of gene expression driven by the H3K27M mutation, we introduced the H3K27M mutation into murine neural stem cells and performed whole genome bisulfite sequencing (WGBS) to evaluate for genes with the greatest differential methylation in their promoter region. These studies identified an abundance of pro-survival genes such a BCL-2, BCL-xL, MCL-1, Caspase-3, and XIAP. Western blot confirmed elevated expression of these pro-survival factors and RNA-Seq of primary human DIPG confirmed increased expression compared to normal brain. PAC-1 is a ...
Diffuse intrinsic pontine glioma (DIPG) is an invasive malignancy of the brainstem that accounts ... more Diffuse intrinsic pontine glioma (DIPG) is an invasive malignancy of the brainstem that accounts for greater than 80% of pediatric brainstem gliomas. In the past 40 years, there have been no significant advances in DIPG treatments and survival, so it remains a leading cause of death from pediatric brain tumors. Nearly 80% of DIPG harbor a point mutation in H3F3A or HIST1H3B, and the presence of this H3.3K27M mutation is inversely correlated with reduced OS, suggesting that epigenetic dysregulation is a key driver to cause the pathogenesis of DIPG. However, it is unclear how the H3.3K27M mutation and the other common alterations in DIPG contribute to tumorigenicity in human neural stem cells. To address the relative contributions of different oncogenic elements to DIPG, we sought to add common DIPG elements in a stepwise fashion to human neural stem cells derived from the developing hindbrain. We chose oncogenic elements that are known to present in DIPG, including the stem cell fact...
Purpose: Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodelin... more Purpose: Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodeling complex, are detected in various types of human malignancies. Loss of ARID1A compromises DNA damage repair. The induced DNA damage burden may increase reliance on PARP-dependent DNA repair of cancer cells to maintain genome integrity and render susceptibility to PARP inhibitor therapy. Experimental Design: Isogenic ARID1A−/− and wild-type cell lines were used for assessing DNA damage response, DNA compactness, and profiling global serine/threonine phosphoproteomic in vivo. A panel of inhibitors targeting DNA repair pathways was screened for a synergistic antitumor effect with irradiation in ARID1A−/− tumors. Results: ARID1A-deficient endometrial cells exhibit sustained levels in DNA damage response, a result further supported by in vivo phosphoproteomic analysis. Our results show that ARID1A is essential for establishing an open chromatin state upon DNA damage, a process required for r...
The sinus node (SN) is located at the apex of the cardiac conduction system, and SN dysfunction (... more The sinus node (SN) is located at the apex of the cardiac conduction system, and SN dysfunction (SND)—characterized by electrical remodeling—is generally attributed to idiopathic fibrosis or ischemic injuries in the SN. SND is associated with increased risk of cardiovascular disorders, including syncope, heart failure, and atrial arrhythmias, particularly atrial fibrillation. One of the histological SND hallmarks is degenerative atrial remodeling that is associated with conduction abnormalities and increased right atrial refractoriness. Although SND is frequently accompanied by increased fibrosis in the right atrium (RA), its molecular basis still remains elusive. Therefore, we investigated whether SND can induce significant molecular changes that account for the structural remodeling of RA. Towards this, we employed a rabbit model of experimental SND, and then compared the genome-wide RNA expression profiles in RA between SND-induced rabbits and sham-operated controls to identify t...
SARS-CoV-2 is an RNA virus whose success as a pathogen relies on its abilities to repurpose host ... more SARS-CoV-2 is an RNA virus whose success as a pathogen relies on its abilities to repurpose host RNA-binding proteins (RBPs) and to evade antiviral RBPs. To uncover the SARS-CoV-2 RNA interactome, we here develop a robust ribonucleoprotein (RNP) capture protocol and identify 109 host factors that directly bind to SARS-CoV-2 RNAs. Applying RNP capture on another coronavirus HCoV-OC43 revealed evolutionarily conserved interactions between coronaviral RNAs and host proteins. Transcriptome analyses and knockdown experiments delineated 17 antiviral RBPs including ZC3HAV1, TRIM25, PARP12, and SHFL and 8 proviral RBPs such as EIF3D and CSDE1 which are responsible for co-opting multiple steps of the mRNA life cycle. This also led to the identification of LARP1, a downstream target of the mTOR signaling pathway, as an antiviral host factor that interacts with the SARS-CoV-2 RNAs. Overall, this study provides a comprehensive list of RBPs regulating coronaviral replication and opens new avenues for therapeutic interventions
Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of ... more Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of c-MYC have the worst clinical prognosis, with only a minority of patients surviving. To address this unmet clinical need, we generated a human neural stem cell model of medulloblastoma that recapitulated the most aggressive subtype phenotypically and by mRNA expression profiling. An in silico analysis of these cells identified mTOR inhibitors as potential therapeutic agents. We hypothesized that the orally bioavailable TORC1/2 kinase inhibitor TAK228 would have activity against MYC-driven medulloblastoma. TAK228 inhibited mTORC1/2, decreased cell growth and caused apoptosis in high-MYC medulloblastoma cell lines. Comprehensive metabolic profiling of medulloblastoma orthotopic xenografts showed upregulation of glutathione compared to matched normal brain. TAK228 suppressed glutathione production. Because glutathione is required to detoxify platinum-containing chemotherapy, we hypothesized that TAK228 would cooperate with carboplatin in medulloblastoma. TAK228 synergized with carboplatin to inhibit cell growth and induce apoptosis and extended survival in orthotopic xenografts of high-MYC medulloblastoma. Brain-penetrant TORC1/2 inhibitors and carboplatin may be an effective combination therapy for high-risk medulloblastoma.
Diffuse Intrinsic Pontine Gliomas (DIPGs) are universally fatal tumors, resistant to the cytotoxi... more Diffuse Intrinsic Pontine Gliomas (DIPGs) are universally fatal tumors, resistant to the cytotoxic effects of all known therapies. We aim to better understand the mechanisms contributing to this resistance to design new combination therapies that will improve DIPG survival. DIPG's aggressive phenotype is driven by the H3K27M oncohistone mutation that leads to global genomic DNA hypomethylation and abnormal gene expression. To identify patterns of gene expression driven by the H3K27M mutation, we introduced the H3K27M mutation into murine neural stem cells and performed whole genome bisulfite sequencing (WGBS) to evaluate for genes with the greatest differential methylation in their promoter region. These studies identified an abundance of pro-survival genes such a BCL-2, BCL-xL, MCL-1, Caspase-3, and XIAP. Western blot confirmed elevated expression of these pro-survival factors and RNA-Seq of primary human DIPG confirmed increased expression compared to normal brain. PAC-1 is a ...
Diffuse intrinsic pontine glioma (DIPG) is an invasive malignancy of the brainstem that accounts ... more Diffuse intrinsic pontine glioma (DIPG) is an invasive malignancy of the brainstem that accounts for greater than 80% of pediatric brainstem gliomas. In the past 40 years, there have been no significant advances in DIPG treatments and survival, so it remains a leading cause of death from pediatric brain tumors. Nearly 80% of DIPG harbor a point mutation in H3F3A or HIST1H3B, and the presence of this H3.3K27M mutation is inversely correlated with reduced OS, suggesting that epigenetic dysregulation is a key driver to cause the pathogenesis of DIPG. However, it is unclear how the H3.3K27M mutation and the other common alterations in DIPG contribute to tumorigenicity in human neural stem cells. To address the relative contributions of different oncogenic elements to DIPG, we sought to add common DIPG elements in a stepwise fashion to human neural stem cells derived from the developing hindbrain. We chose oncogenic elements that are known to present in DIPG, including the stem cell fact...
Purpose: Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodelin... more Purpose: Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodeling complex, are detected in various types of human malignancies. Loss of ARID1A compromises DNA damage repair. The induced DNA damage burden may increase reliance on PARP-dependent DNA repair of cancer cells to maintain genome integrity and render susceptibility to PARP inhibitor therapy. Experimental Design: Isogenic ARID1A−/− and wild-type cell lines were used for assessing DNA damage response, DNA compactness, and profiling global serine/threonine phosphoproteomic in vivo. A panel of inhibitors targeting DNA repair pathways was screened for a synergistic antitumor effect with irradiation in ARID1A−/− tumors. Results: ARID1A-deficient endometrial cells exhibit sustained levels in DNA damage response, a result further supported by in vivo phosphoproteomic analysis. Our results show that ARID1A is essential for establishing an open chromatin state upon DNA damage, a process required for r...
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