Programing, Reprogramming & Psychiatric Diseases
A striking feature of the nervous system is its enormous cellular diversity. The Yang laboratory seeks to understand how the nervous system achieves its extraordinary cellular and functional complexity. To study these fundamental questions and associated brain disorders, we direct the differentiation of stem cells into diverse types of brain cells such as neurons, astrocytes, oligodendrocytes and microglia. Although reductionist in nature, this system allows us to reconstitute human nervous system in a dish and elucidate the underlying signaling interactions, cellular information processing, and gene expression regulation that govern basic activities of cells and coordinates all cell actions.
Our work aims at developing approaches and employ state-of-the-art stem cell biology, genome engineering, and neuroscience approaches to understand and modulate the neuronal function in neuropsychiatric diseases. We use 2D and 3D organoid models to understanding how disease associated risk variants in contribute to pathogenesis of multiple neuropsychiatric disorders including autism spectrum disorder, bipolar disorder and schizophrenia.
Areas of Investigation
Cell fate in the nervous system
We have pioneered the transcription factor mediated (trans-)differentiation of non-neural human cells, including fibroblasts and pluripotent stem cells, into multiple neural lineages including neurons and glial cells. Currently, we are using single cell transcriptome sequencing to elucidate the genetic mechanisms underlying interneuron diversity in transcription factor-directed human stem cell differentiation context and to identify gene modules that may influence the specification of human interneuron subtypes queried in vitro. The ultimate goal is to recreate the cell types of the central nervous system from human pluripotent stem cells for research and potential use in clinical therapies.
Modeling human brain development and disease
One of the most intriguing applications of human pluripotent stem cells is the possibility to recapitulate and study key aspects of human brain development. Our group team up with the Seaver Autism Center at Mount Sinai to investigate the changes caused by autism associated rare mutations at cellular and molecular levels in multiple brain regions using 3D brain organoid models and in different neuronal types with particular interests on epigenetic modifications and synaptic functions using induced neurons.
Non-coding regions and human psychiatric diseases
Advances in human genetics and next-generation sequencing have permitted the identification of a stunning number of genetic variants that are linked to neurological and psychiatric disorders, providing a platform for unraveling the causal chain of events that result in the disorder. However, the availability of data is not synonymous with the presence of meaning. Indeed, the challenge researchers are facing now is the derivation of biological meaning post-GWAS. Particularly, an increasing number of risk-associated variants are found in non-coding sequences. We use stem cell modeling system, CRISPR-mediated genome engineering, promoter capture HiC, and state-of-the-art single-cell sequencing technology to better understand enhancers in disease relevant cell types, including where they reside, how they work and what genes they regulate, which could be a critical resource for furthering our understanding of the human genome and its role in disease.
Nobuta H, Yang N, Ng YH, Marro SG, Sabeur K, Chavali M, Stockley JH, Killilea DW, Walter PB, Zhao C, Huie P Jr, Goldman SA, Kriegstein AR, Franklin RJM, Rowitch DH, Wernig M. Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation. Cell Stem Cell. 2019 Oct 3;25(4):531-541
Marro SG, Chanda S, Yang N, Janas JA, Valperga G, Trotter J, Zhou B, Merrill S, Yousif I, Shelby H, Vogel H, Kalani MYS, Südhof TC, Wernig M. Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons. Neuron. 2019 Aug 21;103(4):617-626.
Yang N, Chanda S, Marro S, Ng YH, Janas JA, Haag D, Ang CE, Tang Y, Flores Q, Mall M, Wapinski O, Li M, Ahlenius H, Rubenstein JL, Chang HY, Buylla AA, Südhof TC, Wernig M. Generation of pure GABAergic neurons by transcription factor programming. Nat Methods. 2017 Jun;14(6):621-628
Marro S, Yang N. Transdifferentiation of mouse fibroblasts and hepatocytes to functional neurons. Methods Mol Biol. 2014;1150:237-46 (book chapter)
Yang N, Wernig M. Harnessing the stem cell potential: a case for neural stem cell therapy. Nat Med. 2013 Dec;19(12):1580-1.
Yang N, Zuchero JB, Ahlenius H, Marro S, Ng YH, Vierbuchen T, Hawkins JS, Geissler R, Barres BA, Wernig M. Generation of oligodendroglial cells by direct lineage conversion. Nat Biotechnol. 2013 May;31(5):434-9.
Yang N, Dong Z, Guo S. Fezf2 Regulates Multilineage Neuronal Differentiation through Activating Basic Helix-Loop-Helix and Homeodomain Genes in the Zebrafish Ventral Forebrain. J Neurosci. 2012 Aug 8;32(32):10940-8.
Dong Z, Yang N, Chitnis A, Guo S. Intra-lineage directional Notch signaling regulates self-renewal ad differentiation of asymmetrically dividing radial glia. Neuron 2012 Apr 12;74(1):65-78.
Yang N, Ng YH, Pang ZP, Südhof TC, Wernig M. Induced neuronal cells: how to make and define a neuron. Cell Stem Cell. 2011 Dec 2;9(6):517-25.
Marro S, Pang ZP, Yang N, Tsai MC, Qu K, Chang HY, Südhof TC, Wernig M. Direct Lineage Conversion of Terminally Differentiated Hepatocytes to Functional Neurons. Cell Stem Cell. 2011 2011 Oct 4;9(4):374-82.
Pang ZP*, Yang N*, Vierbuchen T*, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Südhof TC, Wernig M. Induction of human neuronal cells by defined transcription factors. Nature. 2011 May 26;476(7359):220-3.
Meet the team
Carlos is a graduate student from Development, Regeneration, and Stem Cells [DRS] program and works on elucidating the function of non-coding regulatory elements in human neurons using promoter capture HiC and massive parallel reporter assays (MPRA).
Rachel (Ruiqi) Hu
Ruiqi is a visiting graduate student from Huazhong Agricultural University, who currently works on delineating the differentiation trajectory from human pluripotent stem cells to interneurons in vitro using single cell sequencing and studies how ASD associated mutations impair early brain development using brain organoids.
Xiaoting is a visiting graduate student who works on a joint project with Dr. Zhenyu Yue studying novel autophagy cargoes and adaptors in human induced neurons and their roles in autophagy-lysosome degradation, synaptic vesicle trafficking and protein/lipid kinase signaling.
Gizem Inak Girrbach
Giz is a postdoctoral fellow in neuroscience and stem cell field with a current focus on autism spectrum disorder, aiming to dissect the mechanisms underlying neuronal pathologies. Besides the interest in iPSC culturing and neuronal differentiation, Giz enjoys cooking plant-based recipes, being active outdoors, exploring new places and cultures.
Linda is a postdoctoral fellow in the department of neuroscience. Her project involves the use of iPS cell derived 3D cerebral organoids to investigate the role of NF1 on cellular and molecular mechanisms of early brain development. In her free time, she enjoys dancing, biking, traveling and making ice cream.
Sofia is a postdoctoral fellow mentored by Drs. Joseph Buxbaum and Yang. Her current project uses human cell model to study pathophysiology of FOXP1-related intellectual disability syndrome.
Becky is a postdoctoral fellow mentored by Drs. Joseph Buxbaum and Yang. She uses iPSC and iN models to study the role of the protein DDX3X in human neurons and the impact of pathogenic variants on its normal functions. When not working, Becky enjoys hiking with the husband and their dog, running, and rock climbing.
We welcome postdoctoral applicants who are interested in applying pluripotent stem cell models to address basic mechanistic questions in the development, function and disease of human nervous system. Applicants with expertise in genomics, differentiation of pluripotent stem cells, or neural development/neuroscience are of particular interest at this time. Interested candidates should send their CV and names/contact information of 3 potential references to Dr. Nan Yang.