Yang Laboratory at University of Calgary

OUR PROJECTS The human brain is made up of billions of neurons that are organized into complex circuits for higher-order brain functions. These neurons are produced by neural stem cells in a precise temporal and spatial manner during development. Perturbing the genesis of correct numbers and types of neurons may result in the abnormal assembly of neural circuitry and, ultimately, brain deficits. With a focus on neural stem cells and neurogenesis, our lab is interested in (i) elucidating the molecular and cellular mechanisms involved in building the mammalian brain, and (ii) understanding how genetic and environmental perturbations relevant to neurodevelopmental disorders impinge on these processes to influence brain development and function. To dissect the molecular basis of neurogenesis, we use the mouse cerebral cortex as our model system and take a multidisciplinary strategy that integrates the single-gene approach, genome-wide analysis and computational prediction. This allows us to obtain a comprehensive view of the gene expression landscape at multi-regulatory levels during brain development. By doing this, we aim to identify translational control networks in neural stem cells that, when dysregulated, contribute to the pathogenesis of neurodevelopmental diseases, such as autism spectrum disorders and some rare diseases.

Departments of Medical Genetics, Biochemistry & Molecular Biology Cumming School of Medicine Alberta Children’s Hospital Research Institute Hotchkiss Brain Institute University of Calgary

HS-2229 Health Science Centre 3330 Hospital Drive N.W. Calgary, Alberta Canada T2N 4N1

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How are NPCs regulated for appropriate neurogenesis? Much effort has been made to understand the transcriptional regulation of NPCs during neurogenesis. However, increasing evidence shows that mRNA expression often correlates poorly with protein levels, and that gene regulation at the translational level is equally important for controlling complex cellular functions. In line with this notion, protein synthesis has been found to be altered in some forms of autism due to mutations in genes encoding translational regulators, such as the X-linked familial mental retardation protein FMRP, tuberous sclerosis complex proteins TSC1/2 and the translation initiation factor eIF4E. In the past few years, we identified a group of translational repression complexes in NPCs comprised of the translation regulator eIF4E and its binding partner 4E-T. By binding and translationally suppressing mRNAs that promote neurogenesis, the complex maintains the stem cell state of NPCs while allowing rapid neurogenesis in response to cues that de-repress the complex. This evidence reveals an unexpected transcriptionally-primed state of NPCs and an essential role for translational regulation in enabling appropriate neurogenesis at the correct developmental time. To further elucidate how 4E-T repressive complex in NPCs controls appropriate neurogenesis, we have taken computational prediction and proteomic approaches for identifying regulatory RNA-binding proteins and other putative players in the complex.

The assembly of complex cortical circuits requires diverse subtypes of neurons. The genesis of incorrect neuronal subtypes has been linked to the disorganization of cortical layers observed in children with autism. Different subtypes of cortical neurons (deep or superficial layer neurons) are sequentially generated from NPCs at different timepoints by mechanisms that are poorly understood. It is thought that the sequential expression of subtype specification genes in NPCs directs the generation of corresponding neuronal subtypes. Our finding that translational mechanisms play a key role in general aspects of neurogenesis raised the possibility that translational regulation of subtype specification genes in NPCs might also control the temporal genesis of specific neuronal subtype during development. Using systemic analysis of gene expression at both transcription and translation levels, we aim to identify the gene networks and regulators involved in neuronal subtype specification during brain development.

While the pathogenesis of many neurodevelopmental disorders is likely to involve interactions between genetic vulnerability and environmental factors experienced during the in-utero developmental period, it is still largely unknown how the adverse prenatal environment interacts with genetic risk factors to influence brain development and function. In this regard, we are interested in how the gene-environment interplay regulates NPCs and neurogenesis in the developing brain. As one example, we have recently focused on maternal diabetes, where a toxic metabolite methylglyoxal is increased in the circulation, and its detoxifying enzyme Glo1 has been implicated in autism. We have found that perturbations of the metabolic Glo1-methylglyoxal pathway disturb NPCs, cortical development and, in the longterm, impair adult neurogenesis and cognitive function in offspring.

Development of the mammalian cerebral cortex involves a series of fine-tuned processes, including the generation of proper numbers and subtypes of neurons from neural stem/precursor cells (NPCs), the placement of these neurons into correct cortical layers, and finally the assembly of neural circuits. Interruption of one or more of these steps may result in cortical malformation and/or long-lasting structural consequences for the mature brain, both of which have a substantial impact on cognition. However, the mechanisms that control NPCs to generate correct numbers of diverse neuronal subtypes in the developing brain are still largely unknown. We, therefore, aim to address this question and further ask how disease-relevant genetic and environmental risk factors interact to influence NPCs and developmental neurogenesis to shape brain structure and function. Our current efforts are divided into three major projects.

A Translational Switch for Timely Neurogenesis

How do NPCs maintain the balance of self-renewal and differentiation? We study a group of translational repres-sion complexes that direct neurogenesis by controlling gene expression in NPCs at the level of translation.

Focusing on translational regulations in cortical NPCs, we study how NPCs specify the identity of diverse neuronal subtypes in a temporally specific manner to populate six cortical layers during development.

Gene-Environment Interaction in Brain Development

The prenatal environment has a profound impact on fetal brain development. We are inter- ested in how cell-intrinsic and intrauterine environmental factors interact to affect brain development and function.

Kolaj A, Zahr SK, Wang BS, Krawec T, Kazan H, Yang G, Kaplan DR, Miller FD. (2023). The P-body protein 4E-T represses translation to regulate the balance between cell genesis and establishment of the postnatal NSC pool. Cell Reports. 42(3): 112242. DOI: 10.1016/j.celrep.2023.112242. Kedia S#, Aghanoori MR#, Burns KML, Subha M, Williams L, Wen P, Kopp D, Erickson SL, Harvey EM, Chen X, Hua M, Perez JU, Ishraque F, Yang G. (2022). Ubiquitination and deubiquitination of 4E-T regulate neural progenitor cell maintenance and neurogenesis by controlling P-body formation. Cell Reports. 40(2): 111070. doi:10.1016/j.celrep.2022.111070 Aghanoori MR*, Burns KML, Subha M, Williams L, Hua M, Nobakht F, Krawec T, Yang G*. (2022). Immunohistochemical analysis of the developing mouse cortex. Methods in Cell Biology. 170:31-46. doi:10.1016/bs.mcb.2022.02.005. Elgueta D, Murgas P, Riquelme E, Yang G, Cancino GI. (2022). Consequences of Viral Infection and Cytokine Production During Pregnancy on Brain Development in Offspring. Frontiers in Immunology. 13:816619. doi: 10.3389/fimmu.2022.816619. MacPherson MJ#, Erickson SL#, Kopp D#, Wen P, Aghanoori MR, Kedia S, Burns KML, Vitobello A, Mau-Them FT, Thomas Q, Gold NB, Brucker W, Amlie-Wolf L, Gripp KW, Bodamer O, Faivre L, Muona M, Menzies L, Baptista J, Guegan K, Male A, Wei XC, He G, Long Q, Innes AM*, Yang G*. (2021). Nucleocytoplasmic transport of the RNA-binding protein CELF2 regulates neural stem cell fates. Cell Reports. 35(10), 109226. doi:10.1016/j.celrep.2021.109226 Kedia S, Erickson SL, Yang G. (2021). Analysis of translation in the developing mouse brain using polysome profiling. Journal of Visualized Experiments. 22. doi:10.3791/62088. Rodrigues DC, Harvey E, Suraj R, Erickson S, Mohammad L, Ren M, Liu H, He G, Kaplan D, Ellis J, Yang G. (2020). Methylglyoxal couples metabolic and translational control of Notch signalling in mammalian neural stem cells. Nature Communications. 11. doi:10.1038/s41467-020-15941-2 Zeng Q, Long Z, Zhao Y, Feng M, Luo S, Wang K, Wang Y, Yang G, He G. (2019). Valproic acid stimulates hippocampal neurogenesis via activating the Wnt/β-catenin signaling pathway in the APP/PS1/nestin-GFP triple transgenic mouse model of Alzheimer’s disease. Frontiers Aging Neuroscience. 11: 62. Mohammad L, Wiseman J, Erickson S, Yang G. (2019). Protein synthesis and translational control in neural stem cell development and neurogenesis. The Oxford Handbook of Neuronal Protein Synthesis. doi:10.1093/oxfordhb/9780190686307.013.21. Zahr SK, Yang G, Kazan H, Borrett MJ, Yuzwa SA, Voronova A, Kaplan DR, Miller FD.(2018). A translational repression complex in developing mammalian neural stem cells that regulates neuronal specification. Neuron. 97(3): 520-537. Yang G, Cancino GI, Zahr SK, Guskjolen A, Voronova A, Gallagher D, Frankland PW, Kaplan DR, Miller FD. (2016). A Glo1-methylglyoxal pathway that is perturbed in maternal diabetes regulates embryonic and adult neural stem cell pools in murine offspring. Cell Reports. 17: 1022-1036. Rodrigues DC, Kim DS, Yang G, Zaslavsky K, Ha KC, Mok RS, Ross PJ, Zhao M, Piekna A, Wei W, Blencowe BJ, Morris Q, Ellis J. (2016). MECP2 is post-transcriptionally regulated during human neurodevelopment by combinatorial action of RNA-binding proteins and miRNAs. Cell Reports. 17: 720-734. Amadei G, Zander M, Yang G, Dumelie J, Vessey JP, Lipshitz H, Smibert CA, Kaplan DR, Miller FD. (2015). A Smaug2-based translational repression complex determines the balance between precursor maintenance versus differentiation during mammalian neurogenesis. Journal of Neuroscience. 35: 15666-15681. Yang G, Smibert CA, Kaplan DR, Miller FD. (2014). An eIF4E1/4E-T complex determines the genesis of neurons from precursors by translationally repressing a proneurogenic transcription program. Neuron. 84: 723-739.

Guang Yang, PhD Principal Investigator Canada Research Chair (Tier II, regulatory genomics)

Kaylan Burns Graduate student CIHR Canada Graduate Scholarship Eyes High Doctoral Scholarship

Michelle Hua Graduate student KSMT Rare Diseases Research Scholarship WHD Medical Research Scholarship

Reza Aghanoori, PDF (2020-2023), ACHRI/CSM/CIHR Postdoc Fellowships. Current position: Assistant Professor, National Institute of Genetic Engineering and Biotechnology (NIGEB), Iran Emily Harvey, MSc student (2019-2021), Alberta Graduate Excellence Scholarship Drayden Kopp, MSc student (2019-2021), BMB Research Excellence Award Shreeya Kedia, MSc student (2019-2021), ACHRI Graduate Scholarship, Mitacs Globalink Fellowship, Nominated for the JB Hyne Research Innovation Award Rejitha Suraj, PDF (2019-2020) Lamees Mohammad, MSc student (2018-2020), ACHRI Graduate Scholarship Minghao (Michael) Li, MSc student (2017-2020), co-supervisor: Dr. Quan Long (primary), ACHRI Graduate Scholarship and BMB Graduate Student Scholarship

Maneesha Subha, Research assistant (2021-2022) Sarah Erickson, Research assistant (2017-2022) Brooke Rackel, Research assistant (2018-2019) Melissa MacPherson, visiting scholar (2019) Pengqiang Wen, visiting scholar (2018-2019) Holly Liu, Research assistant (2017)

Isaac Obrigewitsch, University of Calgary (2022-2023), MDSC 417/419 Yuki Ferguson, University of Calgary (2022-2023), MDSC 417/419 Leslie Chan, University of Calgary (2023), MCEM 530 Saad Khalid, Webber Academy (2022), Gold Medal, Calgary Youth Science Fair, Webber Academy Science Fair Saher Raouf, University of Calgary (2022), O'Brien Centre (OCSS) Summer Studentship Award Ayush Jha, University of Calgary (2022), PURE Summer Studentship award Taylor Krawec, University of Calgary (2021-2022), Honours Thesis Isabel Rea, University of Calgary (2021-2022), MDSC 417/419 Noor Alkhateeb, University of Calgary (2021-2022), MDSC 417/419, Honours Thesis Molly Williams, University of Calgary (2021), MDSC507 Michelle Hua, University of Calgary (2019-2021), NSERC USRA Summer Studentship awards, BCEM 528 Kenedi Sandquist, University of Calgary (2020-2021), MDSC528, Honours Thesis Elana Sarabin, University of Calgary (2020-2021), CMMB 528 Andrew Hui, University of Calgary (2019-2020), AIHS Summer Studentship award Ali Alotaibi, University of Calgary (2019-2020), Honours Thesis Abdlaziz Alenezi, University of Calgary (2017-2019), MDSC 417/419, Honours Thesis Keevin Lee, University of Calgary (2017-2019), MDSC 417/419, Honours Thesis Jose Uriel Perez, University of Calgary (2017-2019), MDSC 417/419, Honours Thesis Shaelene Standing, University of Calgary (2019), PURE Summer Studentship award Anna-Maria Ciorogariu-Ivan, Mount Royal University (2019) Jibe Zantua, University of Calgary (2018-2019), MDSC 417/419 Mohammad Behbehani, University of Calgary (2018-2019), MDSC 417/419 Carina Jones, University of Calgary (2018), NSERC USRA Summer Studentship award Joscelyn Wiseman, Acadia University (2018), Queen Elizabeth II award Fatin Ishraque, University of Calgary (2018) Mataea Armstrong, High School Summer Student (2018), Heritage Youth Researcher Summer Program (HYRS) Katherine Liang, High School Summer Student (2017), Heritage Youth Researcher Summer Program (HYRS)

Postdoctoral Fellow/Research Assistant Positions – Gene Regulation in Stem Cell Biology and Brain Development (update: 2023-APR) About the Project: We are seeking a highly motivated postdoctoral scholar and a research assistant to lead projects focusing on stem cell biology and gene regulation. The projects will involve utilizing patient-induced pluripotent stem cells (iPSCs), induced neurons from direct reprogramming, and mouse disease models to develop novel precision medicine approaches for patients with rare neurological disorders. Another avenue of research involves using bioinformatics approaches to analyze transcriptomic and post-transcriptomic data generated from brain tissue samples. Qualifications: - Proficiency in English. - Excellent communication, written and interpersonal skills. - Excellent problem-solving skills, attention to detail, and ability to work independently and as part of a team. - Strong written and verbal communication skills in English. • For the Postdoc position: - PhD or an equivalent degree in neuroscience, molecular biology, biochemistry, cell biology or a related discipline. - Prior research experience in stem cell biology and iPSCs. - Experience in cell reprogramming, mouse genetics, confocal microscopy, and drug development would be highly desirable. - Must be self-motivated, with a keen interest in working on multidisciplinary, translational projects. - A strong research background with first-author publications in related fields. • For the Bioinformatics Research Assistant position: - Bachelor's, Master's or PhD degree in bioinformatics, computational biology, computer science, or a related field. - Strong programming skills in Python, R, etc. - Experience in analyzing genomic and transcriptomic data, such as RNA-seq, ChIP-seq, and/or single-cell sequencing. - Familiarity with bioinformatics tools and databases. - A strong research background with first-author publications in related fields. Application details: The position is available immediately, but the starting date is negotiable. Individuals interested in this opportunity should submit the following via email to "info.yanglab@gmail.com" with the subject line "PDF Position" or "RA Position": 1. Letter of interest 2. Curriculum vitae 3. Any relevant publications About the University of Calgary: The University of Calgary is Canada's leading next-generation university – a living, growing and youthful institution that embraces change and opportunity with a can-do attitude. The University of Calgary inspires and supports discovery, creativity and innovation across all disciplines. For more information, visit ucalgary.ca. About Calgary, Alberta: Calgary, Canada's fastest-growing major city, is vibrant and multicultural, with a population of more than 1.2 million. Situated near the Rocky Mountains, Banff National Park and Lake Louise, Calgary offers a great quality of life and outstanding recreational activities.

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