Kenian Chen

Fourth Affiliated Hospital of Guangxi Medical University

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Eric N. Olson

The University of Texas Southwestern Medical Center

Rhonda Bassel‐Duby

The University of Texas Southwestern Medical Center

Ning Liu

University of Illinois Urbana-Champaign

Lin Xu

The University of Texas Southwestern Medical Center

Akansha M. Shah

The University of Texas Southwestern Medical Center

Yin C. Lin

National Taipei University of Technology

Wei Tan

Affiliated Hospital of Guizhou Medical University

Svetlana Bezprozvannaya

The University of Texas Southwestern Medical Center

John McAnally

The University of Texas Southwestern Medical Center

Glynnis A. Garry

The University of Texas Southwestern Medical Center

Cooperative Institutions

The University of Texas Southwestern Medical Center

129

Southwestern Medical Center

Columbia University

Columbia University Irving Medical Center

Kyoto University

Chinese Academy of Medical Sciences & Peking Union Medical College

Harvard University

Harold C. Simmons Comprehensive Cancer Center

Chinese Academy of Sciences

Sun Yat-sen University

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An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex

Journal of Neuroscience (2014)

Ye Zhang Kenian Chen Steven A. Sloan Mariko L. Bennett Anja R. Scholze

The major cell classes of the brain differ in their developmental processes, metabolism, signaling, and function. To better understand the functions and interactions of the cell types that comprise these classes, we acutely purified representative populations of neurons, astrocytes, oligodendrocyte precursor cells, newly formed oligodendrocytes, myelinating oligodendrocytes, microglia, endothelial cells, and pericytes from mouse cerebral cortex. We generated a transcriptome database for these eight cell types by RNA sequencing and used a sensitive algorithm to detect alternative splicing events in each cell type. Bioinformatic analyses identified thousands of new cell type-enriched genes and splicing isoforms that will provide novel markers for cell identification, tools for genetic manipulation, and insights into the biology of the brain. For example, our data provide clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributable to unique splicing of PKM2 , the gene encoding the glycolytic enzyme pyruvate kinase. This dataset will provide a powerful new resource for understanding the development and function of the brain. To ensure the widespread distribution of these datasets, we have created a user-friendly website ( http://web.stanford.edu/group/barres_lab/brain_rnaseq.html ) that provides a platform for analyzing and comparing transciption and alternative splicing profiles for various cell classes in the brain.

Cell type

10.1523/jneurosci.1860-14.2014

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Citations (4,563)

The histone reader PHF7 cooperates with the SWI/SNF complex at cardiac super enhancers to promote direct reprogramming

Nature Cell Biology (2021)

Glynnis A. Garry Svetlana Bezprozvannaya Kenian Chen Huanyu Zhou Hisayuki Hashimoto

Reprogramming

SWI/SNF

MEF2C

GATA4

Myocardin

10.1038/s41556-021-00668-z

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Citations (54)

The MYC-YBX1 Circuit in Maintaining Stem-like Vincristine-Resistant Cells in Rhabdomyosarcoma

Research Square (Research Square) (2022)

Madeline Fritzke Kenian Chen Weiliang Tang Spencer Stinson Misa Ito

Abstract Rhabdomyosarcoma (RMS) is a devastating pediatric soft tissue sarcoma with no effective therapy for relapsed disease. There is limited knowledge on the mechanisms underlying treatment failures. We demonstrated that treatment of RMS cells with vincristine led to an increase of CD133-positive stem-like resistant cells. By single cell RNAseq analysis, MYC and YBX1 were among the top-scored transcription factors in CD133-high expressing cells. CRISPR/Cas9-mediated targeting of MYC and YBX1 reduced stem-like characteristics and viability of the vincristine-resistant cells. MYC and YBX1 exhibited mutual regulation with MYC binding to the YBX1 promoter and YBX1 binding the MYC mRNA. A MYC inhibitor, MYC361i, synergized with vincristine to reduce tumor growth and deplete the stem-like cells in a zebrafish model of RMS. MYC and YBX expression showed positive correlation in RMS patients. High expression of MYC correlated with poor survival. Targeting the MYC-YBX1 axis represents a promising option for improving survival of RMS patients.

Transcription

10.21203/rs.3.rs-2136187/v1

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Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance

Nature Communications (2021)

Miao Cui Ayhan Atmanli María Gabriela Morales Wei Tan Kenian Chen

Abstract Following injury, cells in regenerative tissues have the ability to regrow. The mechanisms whereby regenerating cells adapt to injury-induced stress conditions and activate the regenerative program remain to be defined. Here, using the mammalian neonatal heart regeneration model, we show that Nrf1, a stress-responsive transcription factor encoded by the Nuclear Factor Erythroid 2 Like 1 (Nfe2l1 ) gene, is activated in regenerating cardiomyocytes. Genetic deletion of Nrf1 prevented regenerating cardiomyocytes from activating a transcriptional program required for heart regeneration. Conversely, Nrf1 overexpression protected the adult mouse heart from ischemia/reperfusion (I/R) injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes from doxorubicin-induced cardiotoxicity and other cardiotoxins. The protective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and redox balance. Our findings reveal that the adaptive stress response mechanism mediated by Nrf1 is required for neonatal heart regeneration and confers cardioprotection in the adult heart.

NRF1

Proteostasis

Cardioprotection

10.1038/s41467-021-25653-w

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Citations (105)

RNA-Seq Characterization of Spinal Cord Injury Transcriptome in Acute/Subacute Phases: A Resource for Understanding the Pathology at the Systems Level

PLoS ONE (2013)

Kenian Chen Shuyun Deng He‐Zuo Lü Yiyan Zheng Guodong Yang

Spinal cord injury (SCI) is a devastating neurological disease without effective treatment. To generate a comprehensive view of the mechanisms involved in SCI pathology, we applied RNA-Sequencing (RNA-Seq) technology to characterize the temporal changes in global gene expression after contusive SCI in mice. We sequenced tissue samples from acute and subacute phases (2 days and 7 days after injury) and systematically characterized the transcriptomes with the goal of identifying pathways and genes critical in SCI pathology. The top enriched functional categories include "inflammation response," "neurological disease," "cell death and survival" and "nervous system development." The top enriched pathways include LXR/RXR Activation and Atherosclerosis Signaling, etc. Furthermore, we developed a systems-based analysis framework in order to identify key determinants in the global gene networks of the acute and sub-acute phases. Some candidate genes that we identified have been shown to play important roles in SCI, which demonstrates the validity of our approach. There are also many genes whose functions in SCI have not been well studied and can be further investigated by future experiments. We have also incorporated pharmacogenomic information into our analyses. Among the genes identified, the ones with existing drug information can be readily tested in SCI animal models. Therefore, in this study we have described an example of how global gene profiling can be translated to identifying genes of interest for functional tests in the future and generating new hypotheses. Additionally, the RNA-Seq enables splicing isoform identification and the estimation of expression levels, thus providing useful information for increasing the specificity of drug design and reducing potential side effect. In summary, these results provide a valuable reference data resource for a better understanding of the SCI process in the acute and sub-acute phases.

RNA-Seq

10.1371/journal.pone.0072567

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Citations (86)

Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy

Journal of Clinical Investigation (2023)

Yichi Zhang Andres Ramirez-Martinez Kenian Chen John McAnally Chunyu Cai

Mutations in genes encoding nuclear envelope proteins lead to diseases known as nuclear envelopathies, characterized by skeletal muscle and heart abnormalities, such as Emery-Dreifuss muscular dystrophy (EDMD). The tissue-specific role of the nuclear envelope in the etiology of these diseases has not been extensively explored. We previously showed that global deletion of the muscle-specific nuclear envelope protein NET39 in mice leads to neonatal lethality due to skeletal muscle dysfunction. To study the potential role of the Net39 gene in adulthood, we generated a muscle-specific conditional knockout (cKO) of Net39 in mice. cKO mice recapitulated key skeletal muscle features of EDMD, including muscle wasting, impaired muscle contractility, abnormal myonuclear morphology, and DNA damage. The loss of Net39 rendered myoblasts hypersensitive to mechanical stretch, resulting in stretch-induced DNA damage. Net39 was downregulated in a mouse model of congenital myopathy, and restoration of Net39 expression through AAV gene delivery extended life span and ameliorated muscle abnormalities. These findings establish NET39 as a direct contributor to the pathogenesis of EDMD that acts by protecting against mechanical stress and DNA damage.

Muscle disorder

Emerin

Contractility

10.1172/jci163333

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Citations (4)

The nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization

Nature Communications (2021)

Andres Ramirez-Martinez Yichi Zhang Kenian Chen Jiwoong Kim Bercin Kutluk Cenik

Lamins and transmembrane proteins within the nuclear envelope regulate nuclear structure and chromatin organization. Nuclear envelope transmembrane protein 39 (Net39) is a muscle nuclear envelope protein whose functions in vivo have not been explored. We show that mice lacking Net39 succumb to severe myopathy and juvenile lethality, with concomitant disruption in nuclear integrity, chromatin accessibility, gene expression, and metabolism. These abnormalities resemble those of Emery-Dreifuss muscular dystrophy (EDMD), caused by mutations in A-type lamins (LMNA) and other genes, like Emerin (EMD). We observe that Net39 is downregulated in EDMD patients, implicating Net39 in the pathogenesis of this disorder. Our findings highlight the role of Net39 at the nuclear envelope in maintaining muscle chromatin organization, gene expression and function, and its potential contribution to the molecular etiology of EDMD.

Envelope (radar)

10.1038/s41467-021-20987-x

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Citations (22)

Dynamic Transcriptional Responses to Injury of Regenerative and Non-regenerative Cardiomyocytes Revealed by Single-Nucleus RNA Sequencing

Developmental Cell (2020)

Miao Cui Zhaoning Wang Kenian Chen Akansha M. Shah Wei Tan

Confusion

10.1016/j.devcel.2020.11.006

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Citations (29)

993 InteractPrint predicts clinically meaningful interactions between cancer epithelial cells and immune cells: lessons from a single-cell breast cancer atlas

Regular and Young Investigator Award Abstracts (2022)

Lily Xu Kaitlyn Saunders Hildur Knútsdóttir Kenian Chen Julia Maués

Background

While immunotherapy has revolutionized the treatment of many solid tumors, the efficacy of immunotherapy regimens is comparatively lower in breast cancer. Immunotherapy efficacy is often negatively correlated with intratumor heterogeneity. Novel breast cancer immunotherapy approaches should leverage how intratumor heterogeneity affects immune cells in the tumor microenvironment. However, current definitions of heterogeneity in breast cancer have limited resolution. Single-cell RNA-seq (scRNA-seq) provides an unprecedented opportunity to further define cancer epithelial cell heterogeneity and identify how it influences immune interactions.

Methods

We generated a novel dataset of 236,363 cells from 119 primary breast tumors biopsied from 88 patients taken from 8 publicly available datasets, currently the largest published scRNA-seq dataset in breast cancer. To define cancer epithelial cell heterogeneity, we performed unsupervised and supervised clustering based on molecular subtype and clinical target expression of all cancer epithelial cells. This identified 10 gene elements (GEs), which reflect molecular features that vary between cancer epithelial cells. Receptor-ligand pairing analysis determined how cells that highly express each GE interact with immune cells. We developed InteractPrint, a score which predicts the predominant tumor-interacting immune cells based on GE composition of a patient9s tumor.

Results

In our dataset, 20% of samples were HER2+, 46% HR+, and 32% TNBC. This dataset was statistically powered to characterize cancer epithelial cell heterogeneity. For the 10 GEs, we predicted interactions with immune cells. GEs with predicted NK cell interactions were resistant to NK cell cytotoxicity. In a spatial transcriptomics dataset, GEs with predicted T cell interactions demonstrated colocalization with CD8+ T cells. To infer GE-immune interactions at the patient level, we developed InteractPrint and assessed its accuracy in predicting response to anti-PD-1 therapy. Across two trials and clinical subtypes, T cell InteractPrint demonstrated significant improvement over PD-L1 in predicting response to anti-PD-1 therapy. In an scRNA-seq dataset of samples from patients treated with pembrolizumab, we observed AUC of 81% for T cell InteractPrint versus 54% for PD-L1. In patients treated with paclitaxel + pembrolizumab in the I-SPY2 trial, we observed AUC of 84% for T cell InteractPrint versus 73% for PD-L1.

Conclusions

We defined intratumor heterogeneity and leveraged it to predict immune cell interactions within a patient's tumor. We developed T cell InteractPrint which captures heterogeneity in cancer epithelial and CD8+ T cell interactions and is predictive of anti-PD-1 therapy response at higher AUC than PD-L1. This provides a path forward for the interpretation of intratumor heterogeneity in a clinically meaningful way.

Cancer Immunotherapy

Tumour heterogeneity

10.1136/jitc-2022-sitc2022.0993

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Parenchymal and stromal tissue regeneration of tooth organ by pivotal signals reinstated in decellularized matrix

Nature Materials (2019)

Ling He Jian Zhou Mo Chen Chyuan-Sheng Lin Sahng G. Kim

Decellularization

Parenchyma

10.1038/s41563-019-0368-6

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Citations (61)