15 results on '"Liu, Siyuan John"'
Search Results
2. Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex
- Author
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Nowakowski, Tomasz J., Bhaduri, Aparna, Pollen, Alex A., Alvarado, Beatriz, Mostajo-Radji, Mohammed A., Di Lullo, Elizabeth, Haeussler, Maximilian, Sandoval-Espinosa, Carmen, Liu, Siyuan John, Velmeshev, Dmitry, Ounadjela, Johain Ryad, Shuga, Joe, Wang, Xiaohui, Lim, Daniel A., West, Jay A., Leyrat, Anne A., Kent, W. James, and Kriegstein, Arnold R.
- Published
- 2017
3. Identification and functional characterization of long non-coding RNAs in development and disease
- Author
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Liu, Siyuan John
- Subjects
Molecular biology ,Systematic biology ,Genetics ,cancer ,crispri ,genomics ,lncRNA ,single cell - Abstract
The human genome produces tens of thousands of long non-coding RNA (lncRNAs), transcripts larger than 200 nt that do not make proteins. Select lncRNAs are established regulators of gene expression in developmental processes and in the etiology of diseases. However, the functions of the vast majority of lncRNAs are unknown. Here we utilize high throughput descriptive and functional genomics to characterize and understand the roles of lncRNAs in development of the human brain and in cancer biology. Starting with deep RNA sequencing (RNA-seq) of developing brain tissues, we comprehensively annotated lncRNA transcript structures in the cerebral cortex, revealing thousands of novel lncRNAs, many of which were antisense or non-polyadenylated. We then applied single cell RNA-seq to quantitatively measure the transcriptomes of individual cells, revealing cell type-specific expression of lncRNAs and surprisingly high abundance of certain lncRNAs (e.g. DLX6-AS1) that appear to be low abundance at the population level, due to cellular heterogeneity in the brain. Combination of single cell RNA-seq and exome-seq were then applied to not only measure RNA expression heterogeneity, but also to map the mutational phylogenies of glioblastoma tumors, revealing a novel deletion in PDGFRA that confers survival advantage. We then developed a CRISPR interference (CRISPRi) platform to systematically repress 16,401 lncRNA loci across seven cancer and non-cancer cell lines, identifying 499 lncRNAs necessary for robust growth and proliferation. The functions of these lncRNAs were exquisitely cell type-specific and correlated with complex transcriptional networks and chromatin architecture. Finally, we applied CRISPRi screening of lncRNAs in combination with ionizing radiation therapy and identified over 200 lncRNAs whose knockdown sensitizes glioblastoma cells to radiation induced cell death. As much as these efforts advance our knowledge of lncRNA biology in development and in disease, they also raise exciting new questions for future inquiry.
- Published
- 2017
4. Tropoelastin Switch and Modulated Endothelial Cell Binding to PTFE
- Author
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Bax, Daniel V., Liu, Siyuan John, McKenzie, David R., Bilek, Marcela M. M., and Weiss, Anthony S.
- Published
- 2011
- Full Text
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5. Logic integration of mRNA signals by an RNAi-based molecular computer
- Author
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Xie, Zhen, Liu, Siyuan John, Bleris, Leonidas, and Benenson, Yaakov
- Published
- 2010
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6. Cancer co-rounds: A novel inpatient multidisciplinary oncology rounding model.
- Author
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Ni, Lisa, Viner, Jennifer, Phuong, Christina, Liu, Siyuan John, Yee, Emily, Petrofsky, Mary, Kwon, Daniel H., Daras, Mariza, Boreta, Lauren, and Brondfield, Sam
- Published
- 2023
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- View/download PDF
7. Epigenetic Activation of Neuronal Gene Expression by JMJD3 is Required for Postnatal and Adult Brain Neurogenesis
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Park, Dae Hwi, Hong, Sung Jun, Salinas, Ryan D., Liu, Siyuan John, Sun, Shawn W., Sgualdino, Jacopo, Testa, Giuseppe, Matzuk, Martin M., Iwamori, Naoki, and Lim, Daniel A.
- Subjects
Homeodomain Proteins ,Jumonji Domain-Containing Histone Demethylases ,Neurogenesis ,Brain ,Gene Expression Regulation, Developmental ,Article ,Mice ,Enhancer Elements, Genetic ,HEK293 Cells ,nervous system ,Neural Stem Cells ,Animals ,Humans ,Promoter Regions, Genetic ,reproductive and urinary physiology ,Cells, Cultured ,Transcription Factors - Abstract
The epigenetic mechanisms that enable lifelong neurogenesis from neural stem cells (NSCs) in the adult mammalian brain are poorly understood. Here we show that JMJD3, a histone H3-lysine 27 (H3K27) demethylase, acts as a critical activator of neurogenesis from adult subventricular zone (SVZ) NSCs. JMJD3 is upregulated in neuroblasts, and Jmjd3-deletion targeted to SVZ NSCs in both developing and adult mice impairs neuronal differentiation. JMJD3 regulates neurogenic gene expression via interaction at not only promoter regions, but also neurogenic enhancer elements. JMJD3 localizes at neural enhancers genome-wide in embryonic brain, and in SVZ NSCs, JMJD3 regulates the I12b enhancer of Dlx2. In Jmjd3-deleted SVZ cells, I12b remains enriched with H3K27me3, and Dlx2-dependent neurogenesis fails. These findings support a model in which JMJD3 and the poised state of key transcriptional regulatory elements comprise an epigenetic mechanism that enables the activation of neurogenic gene expression in adult NSCs throughout life.
- Published
- 2014
8. Single-cell sequencing maps gene expression to mutational phylogenies in PDGF- and EGF-driven gliomas.
- Author
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Müller, Sören, Liu, Siyuan John, Di Lullo, Elizabeth, Malatesta, Martina, Pollen, Alex A, Nowakowski, Tomasz J, Kohanbash, Gary, Aghi, Manish, Kriegstein, Arnold R, Lim, Daniel A, and Diaz, Aaron
- Subjects
- *
GLIOBLASTOMA multiforme , *BRAIN tumors , *PLATELET-derived growth factor , *MOLECULAR phylogeny , *GLIOMAS , *EXOMES - Abstract
Glioblastoma multiforme ( GBM) is the most common and aggressive type of primary brain tumor. Epidermal growth factor ( EGF) and platelet-derived growth factor ( PDGF) receptors are frequently amplified and/or possess gain-of-function mutations in GBM. However, clinical trials of tyrosine-kinase inhibitors have shown disappointing efficacy, in part due to intra-tumor heterogeneity. To assess the effect of clonal heterogeneity on gene expression, we derived an approach to map single-cell expression profiles to sequentially acquired mutations identified from exome sequencing. Using 288 single cells, we constructed high-resolution phylogenies of EGF-driven and PDGF-driven GBMs, modeling transcriptional kinetics during tumor evolution. Descending the phylogenetic tree of a PDGF-driven tumor corresponded to a progressive induction of an oligodendrocyte progenitor-like cell type, expressing pro-angiogenic factors. In contrast, phylogenetic analysis of an EGFR-amplified tumor showed an up-regulation of pro-invasive genes. An in-frame deletion in a specific dimerization domain of PDGF receptor correlates with an up-regulation of growth pathways in a proneural GBM and enhances proliferation when ectopically expressed in glioma cell lines. In-frame deletions in this domain are frequent in public GBM data. [ABSTRACT FROM AUTHOR]
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- 2016
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9. Single-cell analysis of long non-coding RNAs in the developing human neocortex.
- Author
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Liu, Siyuan John, Nowakowski, Tomasz J., Pollen, Alex A., Lui, Jan H., Horlbeck, Max A., Attenello, Frank J., He, Daniel, Weissman, Jonathan S., Kriegstein, Arnold R., Diaz, Aaron A., and Lim, Daniel A.
- Published
- 2016
- Full Text
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10. Pluripotency Factors in Embryonic Stem Cells Regulate Differentiation into Germ Layers
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Thomson, Matt, Liu, Siyuan John, Zou, Ling-Nan, Smith, Zack, Meissner, Alexander, and Ramanathan, Sharad
- Subjects
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PLURIPOTENT stem cells , *EMBRYONIC stem cells , *MOLECULAR cell differentiation , *CELL determination , *GENETIC transcription regulation , *TRANSCRIPTION factors - Abstract
Summary: Cell fate decisions are fundamental for development, but we do not know how transcriptional networks reorganize during the transition from a pluripotent to a differentiated cell state. Here, we asked how mouse embryonic stem cells (ESCs) leave the pluripotent state and choose between germ layer fates. By analyzing the dynamics of the transcriptional circuit that maintains pluripotency, we found that Oct4 and Sox2, proteins that maintain ESC identity, also orchestrate germ layer fate selection. Oct4 suppresses neural ectodermal differentiation and promotes mesendodermal differentiation; Sox2 inhibits mesendodermal differentiation and promotes neural ectodermal differentiation. Differentiation signals continuously and asymmetrically modulate Oct4 and Sox2 protein levels, altering their binding pattern in the genome, and leading to cell fate choice. The same factors that maintain pluripotency thus also integrate external signals and control lineage selection. Our study provides a framework for understanding how complex transcription factor networks control cell fate decisions in progenitor cells. PaperClip: Display Omitted [Copyright &y& Elsevier]
- Published
- 2011
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11. Molecular Identity of Human Outer Radial Glia during Cortical Development.
- Author
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Pollen, Alex A., Nowakowski, Tomasz J., Chen, Jiadong, Retallack, Hanna, Sandoval-Espinosa, Carmen, Nicholas, Cory R., Shuga, Joe, Liu, Siyuan John, Oldham, Michael C., Diaz, Aaron, Lim, Daniel A., Leyrat, Anne A., West, Jay A., and Kriegstein, Arnold R.
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NEURAL stem cells , *NEUROGLIA , *GENE expression , *IMMUNOSTAINING , *CELL migration - Abstract
Summary Radial glia, the neural stem cells of the neocortex, are located in two niches: the ventricular zone and outer subventricular zone. Although outer subventricular zone radial glia may generate the majority of human cortical neurons, their molecular features remain elusive. By analyzing gene expression across single cells, we find that outer radial glia preferentially express genes related to extracellular matrix formation, migration, and stemness, including TNC , PTPRZ1 , FAM107A , HOPX , and LIFR. Using dynamic imaging, immunostaining, and clonal analysis, we relate these molecular features to distinctive behaviors of outer radial glia, demonstrate the necessity of STAT3 signaling for their cell cycle progression, and establish their extensive proliferative potential. These results suggest that outer radial glia directly support the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby enabling the developmental and evolutionary expansion of the human neocortex. [ABSTRACT FROM AUTHOR]
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- 2015
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12. Outer Radial Glia-like Cancer Stem Cells Contribute to Heterogeneity of Glioblastoma.
- Author
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Bhaduri A, Di Lullo E, Jung D, Müller S, Crouch EE, Espinosa CS, Ozawa T, Alvarado B, Spatazza J, Cadwell CR, Wilkins G, Velmeshev D, Liu SJ, Malatesta M, Andrews MG, Mostajo-Radji MA, Huang EJ, Nowakowski TJ, Lim DA, Diaz A, Raleigh DR, and Kriegstein AR
- Subjects
- Adult, Cell Line, Tumor, Ependymoglial Cells, Humans, Neoplastic Stem Cells, Receptor-Like Protein Tyrosine Phosphatases, Class 5, Brain Neoplasms genetics, Glioblastoma genetics
- Abstract
Glioblastoma is a devastating form of brain cancer. To identify aspects of tumor heterogeneity that may illuminate drivers of tumor invasion, we created a glioblastoma tumor cell atlas with single-cell transcriptomics of cancer cells mapped onto a reference framework of the developing and adult human brain. We find that multiple GSC subtypes exist within a single tumor. Within these GSCs, we identify an invasive cell population similar to outer radial glia (oRG), a fetal cell type that expands the stem cell niche in normal human cortex. Using live time-lapse imaging of primary resected tumors, we discover that tumor-derived oRG-like cells undergo characteristic mitotic somal translocation behavior previously only observed in human development, suggesting a reactivation of developmental programs. In addition, we show that PTPRZ1 mediates both mitotic somal translocation and glioblastoma tumor invasion. These data suggest that the presence of heterogeneous GSCs may underlie glioblastoma's rapid progression and invasion., (Published by Elsevier Inc.)
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- 2020
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13. The Long Noncoding RNA Pnky Is a Trans-acting Regulator of Cortical Development In Vivo.
- Author
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Andersen RE, Hong SJ, Lim JJ, Cui M, Harpur BA, Hwang E, Delgado RN, Ramos AD, Liu SJ, Blencowe BJ, and Lim DA
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- Animals, Brain metabolism, Cerebral Cortex metabolism, Female, Interneurons metabolism, Male, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins genetics, Neurogenesis genetics, Neurons metabolism, POU Domain Factors genetics, RNA, Long Noncoding metabolism, Trans-Activators genetics, Trans-Activators metabolism, Transcription Factors metabolism, Cerebral Cortex embryology, Neural Stem Cells metabolism, RNA, Long Noncoding genetics
- Abstract
While it is now appreciated that certain long noncoding RNAs (lncRNAs) have important functions in cell biology, relatively few have been shown to regulate development in vivo, particularly with genetic strategies that establish cis versus trans mechanisms. Pnky is a nuclear-enriched lncRNA that is transcribed divergently from the neighboring proneural transcription factor Pou3f2. Here, we show that conditional deletion of Pnky from the developing cortex regulates the production of projection neurons from neural stem cells (NSCs) in a cell-autonomous manner, altering postnatal cortical lamination. Surprisingly, Pou3f2 expression is not disrupted by deletion of the entire Pnky gene. Moreover, expression of Pnky from a BAC transgene rescues the differential gene expression and increased neurogenesis of Pnky-knockout NSCs, as well as the developmental phenotypes of Pnky-deletion in vivo. Thus, despite being transcribed divergently from a key developmental transcription factor, the lncRNA Pnky regulates development in trans., (Published by Elsevier Inc.)
- Published
- 2019
- Full Text
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14. The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells.
- Author
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Ramos AD, Andersen RE, Liu SJ, Nowakowski TJ, Hong SJ, Gertz C, Salinas RD, Zarabi H, Kriegstein AR, and Lim DA
- Subjects
- Alternative Splicing genetics, Animals, Base Sequence, Cells, Cultured, Embryo, Mammalian, Heterogeneous-Nuclear Ribonucleoproteins genetics, Humans, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Neurogenesis genetics, Polypyrimidine Tract-Binding Protein genetics, RNA, Long Noncoding genetics, RNA, Small Interfering genetics, Brain metabolism, Embryonic Stem Cells physiology, Heterogeneous-Nuclear Ribonucleoproteins metabolism, Neural Stem Cells physiology, Neurons physiology, Polypyrimidine Tract-Binding Protein metabolism, RNA, Long Noncoding metabolism
- Abstract
While thousands of long noncoding RNAs (lncRNAs) have been identified, few lncRNAs that control neural stem cell (NSC) behavior are known. Here, we identify Pinky (Pnky) as a neural-specific lncRNA that regulates neurogenesis from NSCs in the embryonic and postnatal brain. In postnatal NSCs, Pnky knockdown potentiates neuronal lineage commitment and expands the transit-amplifying cell population, increasing neuron production several-fold. Pnky is evolutionarily conserved and expressed in NSCs of the developing human brain. In the embryonic mouse cortex, Pnky knockdown increases neuronal differentiation and depletes the NSC population. Pnky interacts with the splicing regulator PTBP1, and PTBP1 knockdown also enhances neurogenesis. In NSCs, Pnky and PTBP1 regulate the expression and alternative splicing of a core set of transcripts that relates to the cellular phenotype. These data thus unveil Pnky as a conserved lncRNA that interacts with a key RNA processing factor and regulates neurogenesis from embryonic and postnatal NSC populations., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
15. Activation of neuronal gene expression by the JMJD3 demethylase is required for postnatal and adult brain neurogenesis.
- Author
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Park DH, Hong SJ, Salinas RD, Liu SJ, Sun SW, Sgualdino J, Testa G, Matzuk MM, Iwamori N, and Lim DA
- Subjects
- Animals, Brain cytology, Brain growth & development, Cells, Cultured, Enhancer Elements, Genetic, Gene Expression Regulation, Developmental, HEK293 Cells, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Jumonji Domain-Containing Histone Demethylases genetics, Mice, Neural Stem Cells cytology, Neural Stem Cells metabolism, Promoter Regions, Genetic, Transcription Factors genetics, Transcription Factors metabolism, Brain metabolism, Jumonji Domain-Containing Histone Demethylases metabolism, Neurogenesis
- Abstract
The epigenetic mechanisms that enable lifelong neurogenesis from neural stem cells (NSCs) in the adult mammalian brain are poorly understood. Here, we show that JMJD3, a histone H3 lysine 27 (H3K27) demethylase, acts as a critical activator of neurogenesis from adult subventricular zone (SVZ) NSCs. JMJD3 is upregulated in neuroblasts, and Jmjd3 deletion targeted to SVZ NSCs in both developing and adult mice impairs neuronal differentiation. JMJD3 regulates neurogenic gene expression via interaction at not only promoter regions but also neurogenic enhancer elements. JMJD3 localizes at neural enhancers genome-wide in embryonic brain, and in SVZ NSCs, JMJD3 regulates the I12b enhancer of Dlx2. In Jmjd3-deleted SVZ cells, I12b remains enriched with H3K27me3 and Dlx2-dependent neurogenesis fails. These findings support a model in which JMJD3 and the poised state of key transcriptional regulatory elements comprise an epigenetic mechanism that enables the activation of neurogenic gene expression in adult NSCs throughout life., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
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