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126 results on '"Chen, Hsu-Hsin"'

1. Overloading And unpacKing (OAK) - droplet-based combinatorial indexing for ultra-high throughput single-cell multiomic profiling

Author

Wu, Bing, Bennett, Hayley M., Ye, Xin, Sridhar, Akshayalakshmi, Eidenschenk, Celine, Everett, Christine, Nazarova, Evgeniya V., Chen, Hsu-Hsin, Kim, Ivana K., Deangelis, Margaret, Owen, Leah A., Chen, Cynthia, Lau, Julia, Shi, Minyi, Lund, Jessica M., Xavier-Magalhães, Ana, Patel, Neha, Liang, Yuxin, Modrusan, Zora, and Darmanis, Spyros

Published
2024
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2. Systems genomics in age-related macular degeneration

Author

Hollander, Anneke I den, Mullins, Robert F, Orozco, Luz D, Voigt, Andrew P, Chen, Hsu-Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L, Kuiper, Jonas JW, Tumminia, Santa J, Allikmets, Rando, Hageman, Gregory S, Stambolian, Dwight, Klaver, Caroline CW, Boeke, Jef D, Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A, Weber, Bernhard HF, and Gorin, Michael B

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Neurodegenerative, Biotechnology, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Human Genome, Stem Cell Research, Aging, Stem Cell Research - Induced Pluripotent Stem Cell, Macular Degeneration, Neurosciences, Eye Disease and Disorders of Vision, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Generic health relevance, Eye, Humans, Retinal Pigment Epithelium, Complement System Proteins, Choroid, Proteins, Genomics, Polymorphism, Single Nucleotide, Complement Factor H, High-Temperature Requirement A Serine Peptidase 1, Age-related macular degeneration, Omics, Systems genomics, Single cell sequencing, Expression quantitative trait locus, Complement system, iPSc-RPE, Induced pluripotent stem cells, Clinical trial, Polygenic risk scores, Medical Biochemistry and Metabolomics, Opthalmology and Optometry, Ophthalmology & Optometry, Ophthalmology and optometry
Abstract

Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are 'omics' technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic loci C3, CFB, CFI, CFH, and ARMS2/HTRA1 are currently ongoing, and a phase III clinical trial for C3 inhibition recently showed a modest reduction of lesion growth in geographic atrophy. The EYERISK consortium recently developed a genetic test for AMD that allows genotyping of common and rare variants in AMD-associated genes. Polygenic risk scores (PRS) were applied to quantify AMD genetic risk, and may aid in predicting AMD progression. In conclusion, genomic studies represent a turning point in our exploration of AMD. The results of those studies now serve as a driving force for several clinical trials. Expanding to omics and systems genomics will further decipher function and causality from the associations that have been reported, and will enable the development of therapies that will lessen the burden of AMD.

Published
2022

3. A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration

Author

Orozco, Luz D., Owen, Leah A., Hofmann, Jeffrey, Stockwell, Amy D., Tao, Jianhua, Haller, Susan, Mukundan, Vineeth T., Clarke, Christine, Lund, Jessica, Sridhar, Akshayalakshmi, Mayba, Oleg, Barr, Julie L., Zavala, Rylee A., Graves, Elijah C., Zhang, Charles, Husami, Nadine, Finley, Robert, Au, Elizabeth, Lillvis, John H., Farkas, Michael H., Shakoor, Akbar, Sherva, Richard, Kim, Ivana K., Kaminker, Joshua S., Townsend, Michael J., Farrer, Lindsay A., Yaspan, Brian L., Chen, Hsu-Hsin, and DeAngelis, Margaret M.

Published
2023
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5. Integration of eQTL and a Single-Cell Atlas in the Human Eye Identifies Causal Genes for Age-Related Macular Degeneration

Author

Orozco, Luz D., Chen, Hsu-Hsin, Cox, Christian, Katschke, Kenneth J., Jr., Arceo, Rommel, Espiritu, Carmina, Caplazi, Patrick, Nghiem, Sarajane Saturnio, Chen, Ying-Jiun, Modrusan, Zora, Dressen, Amy, Goldstein, Leonard D., Clarke, Christine, Bhangale, Tushar, Yaspan, Brian, Jeanne, Marion, Townsend, Michael J., van Lookeren Campagne, Menno, and Hackney, Jason A.

Published
2020
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6. Overloading And unpacKing (OAK) - droplet-based combinatorial indexing for ultra-high throughput single-cell multiomic profiling

Author

Wu, Bing, primary, Bennett, Hayley M, additional, Ye, Xin, additional, Sridhar, Akshayalakshmi, additional, Eidenschenk, Celine, additional, Everett, Christine, additional, Nazarova, Evgeniya V., additional, Chen, Hsu-Hsin, additional, Kim, Ivana K., additional, Deangelis, Margaret, additional, Owen, Leah A., additional, Chen, Cynthia, additional, Lau, Julia, additional, Shi, Minyi, additional, Lund, Jessica M., additional, Xavier-Magalhaes, Ana, additional, Patel, Neha, additional, Liang, Yuxin, additional, Modrusan, Zora, additional, and Darmanis, Spyros, additional

Published
2024
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10. Systems genomics in age-related macular degeneration

Author

den Hollander, Anneke I., primary, Mullins, Robert F., additional, Orozco, Luz D., additional, Voigt, Andrew P., additional, Chen, Hsu-Hsin, additional, Strunz, Tobias, additional, Grassmann, Felix, additional, Haines, Jonathan L., additional, Kuiper, Jonas J.W., additional, Tumminia, Santa J., additional, Allikmets, Rando, additional, Hageman, Gregory S., additional, Stambolian, Dwight, additional, Klaver, Caroline C.W., additional, Boeke, Jef D., additional, Chen, Hao, additional, Honigberg, Lee, additional, Katti, Suresh, additional, Frazer, Kelly A., additional, Weber, Bernhard H.F., additional, and Gorin, Michael B., additional

Published
2022
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12. Integration of eQTL and a Single-Cell Atlas in the Human Eye Identifies Causal Genes for Age-Related Macular Degeneration

Author

Orozco, Luz D., Chen, Hsu-Hsin, Cox, Christian, Katschke, Kenneth J., Jr., Rommel Arceo, Espiritu, Carmina, Caplazi, Patrick, Nghiem, Sarajane Saturnio, Chen, Ying-Jiun, Modrusan, Zora, Dressen, Amy, Goldstein, Leonard D., Clarke, Christine, Bhangale, Tushar, Yaspan, Brian, Jeanne, Marion, Townsend, Michael J., van Lookeren Campagne, Menno, and Hackney, Jason A.

Published
2023
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15. DAZL regulates Tet1 translation in murine embryonic stem cells

Author

Welling, Maaike, Chen, Hsu‐Hsin, Muñoz, Javier, Musheev, Michael U, Kester, Lennart, Junker, Jan Philipp, Mischerikow, Nikolai, Arbab, Mandana, Kuijk, Ewart, Silberstein, Lev, Kharchenko, Peter V, Geens, Mieke, Niehrs, Christof, van de Velde, Hilde, van Oudenaarden, Alexander, Heck, Albert JR, and Geijsen, Niels

Published
2015
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17. Systems genomics in age-related macular degeneration.

Author

den Hollander, Anneke I, den Hollander, Anneke I, Mullins, Robert F, Orozco, Luz D, Voigt, Andrew P, Chen, Hsu-Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L, Kuiper, Jonas JW, Tumminia, Santa J, Allikmets, Rando, Hageman, Gregory S, Stambolian, Dwight, Klaver, Caroline CW, Boeke, Jef D, Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A, Weber, Bernhard HF, Gorin, Michael B, den Hollander, Anneke I, den Hollander, Anneke I, Mullins, Robert F, Orozco, Luz D, Voigt, Andrew P, Chen, Hsu-Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L, Kuiper, Jonas JW, Tumminia, Santa J, Allikmets, Rando, Hageman, Gregory S, Stambolian, Dwight, Klaver, Caroline CW, Boeke, Jef D, Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A, Weber, Bernhard HF, and Gorin, Michael B

Abstract

Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are 'omics' technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic loci

Published
2022

18. Systems genomics in age-related macular degeneration

Author

Hollander, A.I. den, Mullins, R.F., Orozco, Luz D., Voigt, Andrew P., Chen, Hsu-Hsin, Strunz, Tobias, Klaver, C.C.W., Weber, B.H.F., Gorin, M.B., Hollander, A.I. den, Mullins, R.F., Orozco, Luz D., Voigt, Andrew P., Chen, Hsu-Hsin, Strunz, Tobias, Klaver, C.C.W., Weber, B.H.F., and Gorin, M.B.

Abstract

Contains fulltext : 285289.pdf (Publisher’s version ) (Open Access)

Published
2022

19. Systems genomics in age-related macular degeneration

Author

den Hollander, Anneke I., Mullins, Robert F., Orozco, Luz D., Voigt, Andrew P., Chen, Hsu Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L., Kuiper, Jonas J.W., Tumminia, Santa J., Allikmets, Rando, Hageman, Gregory S., Stambolian, Dwight, Klaver, Caroline C.W., Boeke, Jef D., Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A., Weber, Bernhard H.F., Gorin, Michael B., den Hollander, Anneke I., Mullins, Robert F., Orozco, Luz D., Voigt, Andrew P., Chen, Hsu Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L., Kuiper, Jonas J.W., Tumminia, Santa J., Allikmets, Rando, Hageman, Gregory S., Stambolian, Dwight, Klaver, Caroline C.W., Boeke, Jef D., Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A., Weber, Bernhard H.F., and Gorin, Michael B.

Abstract

Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are ‘omics’ technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic lo

Published
2022

20. Systems genomics in age-related macular degeneration

Author

MS Oogheelkunde, Infection & Immunity, den Hollander, Anneke I, Mullins, Robert F, Orozco, Luz D, Voigt, Andrew P, Chen, Hsu-Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L, Kuiper, Jonas J W, Tumminia, Santa J, Allikmets, Rando, Hageman, Gregory S, Stambolian, Dwight, Klaver, Caroline C W, Boeke, Jef D, Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A, Weber, Bernhard H F, Gorin, Michael B, MS Oogheelkunde, Infection & Immunity, den Hollander, Anneke I, Mullins, Robert F, Orozco, Luz D, Voigt, Andrew P, Chen, Hsu-Hsin, Strunz, Tobias, Grassmann, Felix, Haines, Jonathan L, Kuiper, Jonas J W, Tumminia, Santa J, Allikmets, Rando, Hageman, Gregory S, Stambolian, Dwight, Klaver, Caroline C W, Boeke, Jef D, Chen, Hao, Honigberg, Lee, Katti, Suresh, Frazer, Kelly A, Weber, Bernhard H F, and Gorin, Michael B

Published
2022

22. Human-specific enrichment of schizophrenia risk-genes in callosal neurons of the developing neocortex

Author

Zuccaro, Emanuela, primary, Murek, Vanessa, additional, Kim, Kwanho, additional, Chen, Hsu-Hsin, additional, Mancinelli, Sara, additional, Oyler-Castrillo, Paul, additional, Jiménez-Barrón, Laura T., additional, Gerhardinger, Chiara, additional, Brown, Juliana R., additional, Byrnes, Andrea, additional, Neale, Benjamin M., additional, Levin, Joshua Z., additional, Ziller, Michael J., additional, Lodato, Simona, additional, and Arlotta, Paola, additional

Published
2021
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28. Novel tau fragments in cerebrospinal fluid: relation to tangle pathology and cognitive decline in Alzheimer’s disease

Author

Cicognola, Claudia, primary, Brinkmalm, Gunnar, additional, Wahlgren, Jessica, additional, Portelius, Erik, additional, Gobom, Johan, additional, Cullen, Nicholas C., additional, Hansson, Oskar, additional, Parnetti, Lucilla, additional, Constantinescu, Radu, additional, Wildsmith, Kristin, additional, Chen, Hsu-Hsin, additional, Beach, Thomas G., additional, Lashley, Tammaryn, additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, and Höglund, Kina, additional

Published
2018
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30. [P4–099]: CHANGES IN TAU PROTEIN LANDSCAPE DURING ALZHEIMER's DISEASE PROGRESSION

Author

Chen, Hsu‐Hsin, primary, Auger, Paul, additional, Liu, Peter, additional, Lee, Julie, additional, Adolfsson, Oskar, additional, Pihlgren, Maria, additional, Muhs, Andreas, additional, Pfeifer, Andrea, additional, Schauer, Stephen, additional, Baker, Dana, additional, Datwani, Akash, additional, Wildsmith, Kristin R., additional, Beach, Thomas G., additional, and van der Brug, Marcel P., additional

Published
2017
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31. Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons

Author

Lodato, Simona, Zuccaro, Emanuela, Chen, Hsu-Hsin, Yuan, Wen, Meleski, Alyssa, Takahashi, Emi, Mahony, Shaun, Gifford, David K, Arlotta, Paola, Molyneaux, Bradley J., Goff, Loyal A., Rinn, John L., Gifford, David K., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Goff, Loyal A., Mahony, Shaun, and Gifford, David K.

Subjects
Pyramidal Tracts, Mice, Transgenic, Nerve Tissue Proteins, Biology, Identity (music), chemistry.chemical_compound, Mice, Animals, Neurotransmitter, Genes, Suppressor, Promoter Regions, Genetic, Gene, Transcription factor, Progenitor, Mice, Knockout, Motor Neurons, Neurotransmitter Agents, General Neuroscience, Cell identity, Gene expression profiling, DNA-Binding Proteins, chemistry, nervous system, Gene Expression Regulation, Neuroscience, Signal Transduction
Abstract

The neocortex contains an unparalleled diversity of neuronal subtypes, each defined by distinct traits that are developmentally acquired under the control of subtype-specific and pan-neuronal genes. The regulatory logic that orchestrates the expression of these unique combinations of genes is unknown for any class of cortical neuron. Here, we report that Fezf2 is a selector gene able to regulate the expression of gene sets that collectively define mouse corticospinal motor neurons (CSMN). We find that Fezf2 directly induces the glutamatergic identity of CSMN via activation of Vglut1 (Slc17a7) and inhibits a GABAergic fate by repressing transcription of Gad1. In addition, we identify the axon guidance receptor EphB1 as a target of Fezf2 necessary to execute the ipsilateral extension of the corticospinal tract. Our data indicate that co-regulated expression of neuron subtype–specific and pan-neuronal gene batteries by a single transcription factor is one component of the regulatory logic responsible for the establishment of CSMN identity.

Published
2014

34. DAZL regulates Tet1 translation in murine embryonic stem cells

Author

Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Faculty of Veterinary Medicine Research Groups, CSCA TR1, Welling, Maaike, Chen, Hsu Hsin, Munoz Peralta, Javier, Musheev, Michael U., Kester, Lennart, Junker, Jan Philipp, Mischerikow, Nikolai, Arbab, Mandana, Kuijk, Ewart, Silberstein, Lev, Kharchenko, Peter V., Geens, Mieke, Niehrs, Christof, Van De Velde, Hilde, Van Oudenaarden, Alexander, Heck, Albert J R, Geijsen, Niels, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Faculty of Veterinary Medicine Research Groups, CSCA TR1, Welling, Maaike, Chen, Hsu Hsin, Munoz Peralta, Javier, Musheev, Michael U., Kester, Lennart, Junker, Jan Philipp, Mischerikow, Nikolai, Arbab, Mandana, Kuijk, Ewart, Silberstein, Lev, Kharchenko, Peter V., Geens, Mieke, Niehrs, Christof, Van De Velde, Hilde, Van Oudenaarden, Alexander, Heck, Albert J R, and Geijsen, Niels

Published
2015

35. DAZL regulates Tet1 translation in murine embryonic stem cells

Author

CMM Groep Cuppen, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, Cancer, Welling, Maaike, Chen, Hsu-Hsin, Muñoz, Javier, Musheev, Michael U, Kester, Lennart, Junker, Jan Philipp, Mischerikow, Nikolai, Arbab, Mandana, Kuijk, Ewart, Silberstein, Lev, Kharchenko, Peter V, Geens, Mieke, Niehrs, Christof, van de Velde, Hilde, van Oudenaarden, Alexander, Heck, Albert J R, Geijsen, Niels, CMM Groep Cuppen, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, Cancer, Welling, Maaike, Chen, Hsu-Hsin, Muñoz, Javier, Musheev, Michael U, Kester, Lennart, Junker, Jan Philipp, Mischerikow, Nikolai, Arbab, Mandana, Kuijk, Ewart, Silberstein, Lev, Kharchenko, Peter V, Geens, Mieke, Niehrs, Christof, van de Velde, Hilde, van Oudenaarden, Alexander, Heck, Albert J R, and Geijsen, Niels

Published
2015

36. Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons

Author

Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Goff, Loyal A., Mahony, Shaun, Gifford, David K., Lodato, Simona, Zuccaro, Emanuela, Chen, Hsu-Hsin, Yuan, Wen, Meleski, Alyssa, Takahashi, Emi, Gifford, David K, Arlotta, Paola, Molyneaux, Bradley J., Rinn, John L., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Goff, Loyal A., Mahony, Shaun, Gifford, David K., Lodato, Simona, Zuccaro, Emanuela, Chen, Hsu-Hsin, Yuan, Wen, Meleski, Alyssa, Takahashi, Emi, Gifford, David K, Arlotta, Paola, Molyneaux, Bradley J., and Rinn, John L.

Abstract

The neocortex contains an unparalleled diversity of neuronal subtypes, each defined by distinct traits that are developmentally acquired under the control of subtype-specific and pan-neuronal genes. The regulatory logic that orchestrates the expression of these unique combinations of genes is unknown for any class of cortical neuron. Here, we report that Fezf2 is a selector gene able to regulate the expression of gene sets that collectively define mouse corticospinal motor neurons (CSMN). We find that Fezf2 directly induces the glutamatergic identity of CSMN via activation of Vglut1 (Slc17a7) and inhibits a GABAergic fate by repressing transcription of Gad1. In addition, we identify the axon guidance receptor EphB1 as a target of Fezf2 necessary to execute the ipsilateral extension of the corticospinal tract. Our data indicate that co-regulated expression of neuron subtype–specific and pan-neuronal gene batteries by a single transcription factor is one component of the regulatory logic responsible for the establishment of CSMN identity.

Published
2015

37. A novel blastocyst-derived stem cell line reveals an active role for growth factor signaling in the induction of stem cell pluripotency

Author

Chou, Yu-Fen, Chen, Hsu-Hsin, Eijpe, Maureen, Yabuuchi, Akiko, Chenoweth, Joshua G., Lu, Jun, McKay, Ronald D.G., and Geijsen, Niels

Subjects
Pluripotent Stem Cells, Cell Culture Techniques, Cell Differentiation, Bone Morphogenetic Protein 4, Cadherins, Embryo, Mammalian, Article, Cell Line, Mice, Blastocyst, embryonic structures, Animals, Intercellular Signaling Peptides and Proteins, Germ Layers
Abstract

Pluripotent stem cell lines can be derived from blastocyst embryos, which yield embryonic stem cell lines (ES cells), as well as the postimplantation epiblast, which gives rise to epiblast stem cell lines (EpiSCs). Remarkably, ES cells and EpiSCs display profound differences in the combination of growth factors that maintain their pluripotent state. Molecular and functional differences between these two stem cell types demonstrate that the tissue of origin and/or the growth factor milieu may be important determinants of the stem cell identity. We explored how developmental stage of the tissue of origin and culture growth factor conditions affect the stem cell pluripotent state. Our findings indicate that novel stem cell lines, with unique functional and molecular properties, can be generated from murine blastocyst embryos. We demonstrate that the culture growth factor environment and cell-cell interaction play a critical role in defining several unique and stable stem cell ground states.

Published
2008

40. DAZL limits pluripotency, differentiation, and apoptosis in developing primordial germ cells

Author

Sub Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Onderzoek, Biomolecular Mass Spectrometry and Proteomics, Molecular Pharmacy, Chen, Hsu-Hsin, Welling, Maaike, Bloch, Donald B, Muñoz, Javier, Mientjes, Edwin, Chen, Xinjie, Tramp, Cody, Wu, Jie, Yabuuchi, Akiko, Chou, Yu-Fen, Buecker, Christa, Krainer, Adrian, Willemsen, Rob, Heck, Albert J, Geijsen, Niels, Sub Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Onderzoek, Biomolecular Mass Spectrometry and Proteomics, Molecular Pharmacy, Chen, Hsu-Hsin, Welling, Maaike, Bloch, Donald B, Muñoz, Javier, Mientjes, Edwin, Chen, Xinjie, Tramp, Cody, Wu, Jie, Yabuuchi, Akiko, Chou, Yu-Fen, Buecker, Christa, Krainer, Adrian, Willemsen, Rob, Heck, Albert J, and Geijsen, Niels

Published
2014

41. The Polycomb Group Protein L3mbtl2 Assembles an Atypical PRC1-Family Complex that Is Essential in Pluripotent Stem Cells and Early Development

Author

Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Young, Richard A., Whyte, Warren A., Qin, Jinzhong, Anderssen, Endre, Apostolou, Effie, Chen, Hsu-Hsin, Akbarian, Schahram, Bronson, Roderick T., Hochedlinger, Konrad, Ramaswamy, Sridhar, Hock, Hanno, Whyte, Warren Anthony, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Young, Richard A., Whyte, Warren A., Qin, Jinzhong, Anderssen, Endre, Apostolou, Effie, Chen, Hsu-Hsin, Akbarian, Schahram, Bronson, Roderick T., Hochedlinger, Konrad, Ramaswamy, Sridhar, Hock, Hanno, and Whyte, Warren Anthony

Abstract

L3mbtl2 has been implicated in transcriptional repression and chromatin compaction but its biological function has not been defined. Here we show that disruption of L3mbtl2 results in embryonic lethality with failure of gastrulation. This correlates with compromised proliferation and abnormal differentiation of L3mbtl2−/− embryonic stem (ES) cells. L3mbtl2 regulates genes by recruiting a Polycomb Repressive Complex1 (PRC1)-related complex, resembling the previously described E2F6-complex, and including G9A, Hdac1, and Ring1b. The presence of L3mbtl2 at target genes is associated with H3K9 dimethylation, low histone acetylation, and H2AK119 ubiquitination, but the latter is neither dependent on L3mbtl2 nor sufficient for repression. Genome-wide studies revealed that the L3mbtl2-dependent complex predominantly regulates genes not bound by canonical PRC1 and PRC2. However, some developmental regulators are repressed by the combined activity of all three complexes. Together, we have uncovered a highly selective, essential role for an atypical PRC1-family complex in ES cells and early development., Ellison Medical Foundation (MGH start-up funds), Massachusetts General Hospital (Federal Share of the Program Income, C06 CA059267), Loma Linda University. Medical Center (James M. Slater Proton Treatment and Research Center), Vanderbilt University (Silvio O. Conte Center, ‘‘Epigenetic Mechanisms of Depression’’(P50MH09689001)), Massachusetts General Hospital (MGH ECOR Fund for Medical Discovery Award)

Published
2014

42. An ES-Like Pluripotent State in FGF-Dependent Murine iPS cells

Author

Di Stefano, Bruno, primary, Buecker, Christa, additional, Ungaro, Federica, additional, Prigione, Alessandro, additional, Chen, Hsu-Hsin, additional, Welling, Maaike, additional, Eijpe, Maureen, additional, Mostoslavsky, Gustavo, additional, Tesar, Paul, additional, Adjaye, James, additional, Geijsen, Niels, additional, and Broccoli, Vania, additional

Published
2010
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50. Calpain-mediated tau fragmentation is altered in Alzheimer's disease progression

Author

Chen, Hsu-Hsin, Liu, Peter, Auger, Paul, Lee, Seung-Hye, Adolfsson, Oskar, Rey-Bellet, Lorianne, Lafrance-Vanasse, Julien, Friedman, Brad A., Pihlgrens, Maria, Muhs, Andreas, Pfeifer, Andrea, Ernst, James, Ayalon, Gai, Wildsmith, Kristin R., Beach, Thomas G., and van der Brug, Marcel P.

Subjects
proteolysis, rat-brain, neurofibrillary tangles, traumatic brain-injury, neurodegeneration, neutral proteinase calpain, paired helical filaments, pathology, cleavage, in-vivo
Abstract

The aggregation of intracellular tau protein is a major hallmark of Alzheimer's disease (AD). The extent and the stereotypical spread of tau pathology in the AD brain are correlated with cognitive decline during disease progression. Here we present an in-depth analysis of endogenous tau fragmentation in a well-characterized cohort of AD and age-matched control subjects. Using protein mass spectrometry and Edman degradation to interrogate endogenous tau fragments in the human brain, we identified two novel proteolytic sites, G323 and G326, as major tau cleavage events in both normal and AD cortex. These sites are located within the sequence recently identified as the structural core of tau protofilaments, suggesting an inhibitory mechanism of fibril formation. In contrast, a different set of novel cleavages showed a distinct increase in late stage AD. These disease-associated sites are located outside of the protofi lament core sequence. We demonstrate that calpain 1 specifically cleaves at both the normal and diseased sites in vitro, and the site selection is conformation-dependent. Monomeric tau is predominantly cleaved at G323/G326 (normal sites), whereas oligomerization increases cleavages at the late-AD-associated sites. The fragmentation patterns specific to disease and healthy states suggest novel regulatory mechanisms of tau aggregation in the human brain.

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