Anna Szekely, MD
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Research Summary
My research interest focuses on how genes and genetic mechanisms contribute to childhood developmental or late-onset disorders of the human nervous system. State-of-the art technologies are used to investigate global molecular changes that arise during neuronal fate specification and differentiation from pluripotent embryonic stem (ES) cells. To gain new insights into pathogenesis of specific neurological and neurodevelopmental disorders, such as autism, pluripotent stem cells are derived by reprogramming of differentiated, mature cells of affected patients. Exploring the genetic, molecular and biological features of neural differentiation process from embryonic and patient-specific stem cells may offer an unprecedented chance to understand normal and abnormal human brain development and diseases, with implications for drug development and potential cellular replacement therapy.
Extensive Research Description
A deep commitment to academic medicine has fundamentally influenced my research interests, from years of basic molecular neuroscience research to becoming a double-boarded physician in Adult Neurology and Clinical Genetics with a continuing involvement in basic and translational research. My early studies focused on how conserved genetic programs can change in mature neurons in response to specific, transmitter-receptor mediated signals. The realization, that dynamic alteration of genetic programs may also play a fundamental role in pathological processes, led to my focus on how various layers of genomic architecture are influencing a phenotype in health and disease.
1. Exploitation of rare genetic disorders with Mendelian trait may provide novel insights into mechanisms of common disorders and complex biological processes, such as dementia, diabetes or aging, and recognized disease pathways can offer strategies for prevention, diagnosis, and therapy.
Among the simple Mendelian disorders of humans, Werner syndrome most closely resembles an acceleration of normal aging. In prior studies I demonstrated that WRN protein directly interacts with the DNA replication machinery. To define better cellular events that are specifically vulnerable to WRN deficiency, I used RNA interference (RNAi) to silence the expression of Wrn gene and other RecQ helicases, linked to different clinical phenotypes, in primary human fibroblasts. The series of investigations strongly suggest that defects in DNA repair of specific lesions produced by oxidative damage in slowly dividing or non-dividing cells account for those unique aspects of Werner syndrome that mimic normal aging. We also propose that over time these DNA lesions would also accumulate in stem/precursor cells impairing their replicative capacity, thereby contributing to the complex aging phenotype. Our observations attest to the concept that in metazoan models of aging most pathology occurs in organs made up of slowly dividing or non-dividing cells and that impaired DNA repair and genomic instability, driven by oxidative damage, may underlie normal human aging. These studies further fostered some of the current projects to understand the role of oxygen environment on stem cell pluripotency, stem cell aging and neural lineage specification.
2. Genetic mapping, identifying contributing gene mutations and variants, is only an initial step toward biological understanding of rare or common diseases. Creation of disease models, both in human cell culture and animals, is crucial. Human embryonic stem (hES) cells offer an unprecedented access to the earliest stage of development and modeling cell fate and function. In particular, molecular changes that arise during neuronal differentiation and fate specification can be elucidated that may offer key understanding of normal and abnormal human neural development and disease processes.
We are using a multifaceted approach with investigators of the Yale Stem Cell Center, integrating genomic, proteomic, and genetic experiments to elucidate the molecular events that control neural cell differentiation using hES cells as model system. We have analyzed global transcriptome changes that occur during the early differentiation of human embryonic stem cells (hESCs) into the neural lineage. Next generation, state-of-the-art sequencing analysis revealed a remarkable complexity in gene transcription and splicing dynamics during neural cell differentiation with a wealth of previously unannotated novel transcripts and spliced isoforms specific for each stage of differentiation. My current efforts are focused on a novel type of unbiased, genome-wide functional screen to identify genetic mechanisms that control the steps of the neural differentiation in hES cells. These studies and the platform would offer targets for more downstream goals, including mechanistic investigations or drug discovery.
Further, in a collaborative project within Yale, we investigate the effect of hypoxia in neural stem cell function to identify key genes and their networks that enable neuronal stem cells to repair the injured brain in mouse model of perinatal hypoxia and elucidate the role of these genes for human neuronal stem cell function. The project may provide clues how to promote neuronal stem cell regenerative potential in traumatic, vascular and degenerative disorders of the human brain.
3. To understand the genetic and molecular underpinnings of neurological and neurodevelopmental disorders, we capitalize on the recent technical development of reprogramming adult, differentiated somatic cells to pluripotent stem cells. These induced pluripotent stem (iPS) cells can be derived with a specific genetic and disease background and can differentiate into essentially any cell types of the body. Thus, by using patient-specific cells one may gain knowledge of key molecular players and abnormalities of neural fate determination and function to understand monogenic or complex developmental and degenerative brain disorders. This would not be otherwise possible to do in living CNS.
With other Yale investigators with interest in neurogenetics, we have recently launched the Program in Neurodevelopment and Regeneration and began to generate iPS cell lines derived directly from patients with various neurodevelopmental disorders with notable genetic component, such as autism spectrum disorders (ASD). We are particularly interested to understand if macrocephaly, a well replicated phenotype in ASD, may be related to intrinsic alterations neuronal stem cell properties governing cell proliferation and/or neural and glial differentiation and how these processes align with the patient-specific genomic architecture. Advanced technologies are used to reprogram skin cells, obtain data on patient-specific DNA variations and integrate with quantitative gene expression information and correlative epigenetic regulatory marks along with phenotypic analysis of neural differentiation. These projects may provide an exceptional chance to understand the genetic and cellular mechanisms underlying this complex disorder and also to correlate with the clinical phenotype. As a model in general, iPS cells provide an invaluable resource for in vitro disease modeling, pharmaceutical screening (drugs/small molecules) and potential for cell-replacement therapy.
4. Having the opportunity to clinically evaluate patients with rare neurogenetic conditions, I interact regularly with scientists of the field to pursue molecular studies. I am particularly interested to contribute to the ongoing gene discovery efforts at Yale for autism, mental retardation and disorders of brain malformations, among others.
- Integrated approach to neural differentiation of human embryonic stem (hES) cells - use the latest advances in large-scale genomic and proteomic approaches to decipher critical elements of neuronal differentiation from human embryonic stem (ES) cells. Genes and pathways identified by these studies provide a basis for mechanistic investigations, construction of model biological networks and drug discovery.
- Cellular and genetic determinants of increased head size in autism - novel genetic, genomic and morphological approaches are used in this collaborative project to study neuronal differentiation of induced pluripotent stem (iPS) cells derived from patients with autism spectrum disorder. The project provides an unprecedented chance to understand the biological mechanisms of this disease.
- Effect of hypoxia on neural stem cell function in mouse and human - this collaborative project aims to identify key genes and their networks that enable neuronal stem cells to repair the injured brain in mouse model of perinatal hypoxia and elucidate their role for human neuronal stem cell function. The project may uncover how to promote neuronal stem cell regenerative potential in traumatic, vascular and degenerative disorders of the human brain.
Coauthors
Research Interests
Genetic Variation; Genetic Predisposition to Disease; Gene Silencing; Neurogenesis
Selected Publications
- Author Correction: Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesisJourdon A, Wu F, Mariani J, Capauto D, Norton S, Tomasini L, Amiri A, Suvakov M, Schreiner J, Jang Y, Panda A, Nguyen C, Cummings E, Han G, Powell K, Szekely A, McPartland J, Pelphrey K, Chawarska K, Ventola P, Abyzov A, Vaccarino F. Author Correction: Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis. Nature Neuroscience 2023, 26: 2035-2035. PMID: 37674007, DOI: 10.1038/s41593-023-01447-9.
- Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesisJourdon A, Wu F, Mariani J, Capauto D, Norton S, Tomasini L, Amiri A, Suvakov M, Schreiner J, Jang Y, Panda A, Nguyen C, Cummings E, Han G, Powell K, Szekely A, McPartland J, Pelphrey K, Chawarska K, Ventola P, Abyzov A, Vaccarino F. Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis. Nature Neuroscience 2023, 26: 1505-1515. PMID: 37563294, PMCID: PMC10573709, DOI: 10.1038/s41593-023-01399-0.
- Efficient reconstruction of cell lineage trees for cell ancestry and cancerJang Y, Fasching L, Bae T, Tomasini L, Schreiner J, Szekely A, Fernandez T, Leckman J, Vaccarino F, Abyzov A. Efficient reconstruction of cell lineage trees for cell ancestry and cancer. Nucleic Acids Research 2023, 51: e57-e57. PMID: 37026484, PMCID: PMC10250207, DOI: 10.1093/nar/gkad254.
- Characterization of human basal ganglia organoidsBrady M, Mariani J, Koca Y, Szekely A, King R, Bloch M, Landeros-Weisenberger A, Leckman J, Vaccarino F. Characterization of human basal ganglia organoids. Molecular Psychiatry 2022, 27: 4823-4823. PMID: 36536052, DOI: 10.1038/s41380-022-01914-y.
- Mispatterning and interneuron deficit in Tourette Syndrome basal ganglia organoidsBrady M, Mariani J, Koca Y, Szekely A, King R, Bloch M, Landeros-Weisenberger A, Leckman J, Vaccarino F. Mispatterning and interneuron deficit in Tourette Syndrome basal ganglia organoids. Molecular Psychiatry 2022, 27: 5007-5019. PMID: 36447010, PMCID: PMC9949887, DOI: 10.1038/s41380-022-01880-5.
- Miglustat Therapy for SCARB2-Associated Action Myoclonus–Renal Failure SyndromeQuraishi IH, Szekely AM, Shirali AC, Mistry PK, Hirsch LJ. Miglustat Therapy for SCARB2-Associated Action Myoclonus–Renal Failure Syndrome. Neurology Genetics 2021, 7: e614. PMID: 34337151, PMCID: PMC8320328, DOI: 10.1212/nxg.0000000000000614.
- Early developmental asymmetries in cell lineage trees in living individualsFasching L, Jang Y, Tomasi S, Schreiner J, Tomasini L, Brady MV, Bae T, Sarangi V, Vasmatzis N, Wang Y, Szekely A, Fernandez TV, Leckman JF, Abyzov A, Vaccarino FM. Early developmental asymmetries in cell lineage trees in living individuals. Science 2021, 371: 1245-1248. PMID: 33737484, PMCID: PMC8324008, DOI: 10.1126/science.abe0981.
- Ring chromosome formation by intra‐strand repairing of subtelomeric double stand breaks and clinico‐cytogenomic correlations for ring chromosome 9Chai H, Ji W, Wen J, DiAdamo A, Grommisch B, Hu Q, Szekely AM, Li P. Ring chromosome formation by intra‐strand repairing of subtelomeric double stand breaks and clinico‐cytogenomic correlations for ring chromosome 9. American Journal Of Medical Genetics Part A 2020, 182: 3023-3028. PMID: 32978894, DOI: 10.1002/ajmg.a.61890.
- Hereditary spastic paraplegia presenting as limb dystonia with a rare SPG7 mutation.Schaefer SM, Szekely AM, Moeller JJ, Tinaz S. Hereditary spastic paraplegia presenting as limb dystonia with a rare SPG7 mutation. Neurology Clinical Practice 2018, 8: e49-e50. PMID: 30588391, PMCID: PMC6294529, DOI: 10.1212/cpj.0000000000000552.
- Effective Treatment of Paroxysmal Nonkinesigenic Dyskinesia With OxcarbazepineKumar A, Szekely A, Jabbari B. Effective Treatment of Paroxysmal Nonkinesigenic Dyskinesia With Oxcarbazepine. Clinical Neuropharmacology 2016, 39: 201-205. PMID: 27046658, DOI: 10.1097/wnf.0000000000000149.
- FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum DisordersMariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L, Amenduni M, Szekely A, Palejev D, Wilson M, Gerstein M, Grigorenko EL, Chawarska K, Pelphrey KA, Howe JR, Vaccarino FM. FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders. Cell 2015, 162: 375-390. PMID: 26186191, PMCID: PMC4519016, DOI: 10.1016/j.cell.2015.06.034.
- Primary dystonias and genetic disorders with dystonia as clinical feature of the diseaseMoghimi N, Jabbari B, Szekely AM. Primary dystonias and genetic disorders with dystonia as clinical feature of the disease. European Journal Of Paediatric Neurology 2013, 18: 79-105. PMID: 23911094, DOI: 10.1016/j.ejpn.2013.05.015.
- Functional genomic screen of human stem cell differentiation reveals pathways involved in neurodevelopment and neurodegenerationZhang Y, Schulz VP, Reed BD, Wang Z, Pan X, Mariani J, Euskirchen G, Snyder MP, Vaccarino FM, Ivanova N, Weissman SM, Szekely AM. Functional genomic screen of human stem cell differentiation reveals pathways involved in neurodevelopment and neurodegeneration. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 12361-12366. PMID: 23836664, PMCID: PMC3725080, DOI: 10.1073/pnas.1309725110.
- Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cellsAbyzov A, Mariani J, Palejev D, Zhang Y, Haney MS, Tomasini L, Ferrandino AF, Rosenberg Belmaker LA, Szekely A, Wilson M, Kocabas A, Calixto NE, Grigorenko EL, Huttner A, Chawarska K, Weissman S, Urban AE, Gerstein M, Vaccarino FM. Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 2012, 492: 438-442. PMID: 23160490, PMCID: PMC3532053, DOI: 10.1038/nature11629.
- A highly integrated and complex PPARGC1A transcription factor binding network in HepG2 cellsCharos AE, Reed BD, Raha D, Szekely AM, Weissman SM, Snyder M. A highly integrated and complex PPARGC1A transcription factor binding network in HepG2 cells. Genome Research 2012, 22: 1668-1679. PMID: 22955979, PMCID: PMC3431484, DOI: 10.1101/gr.127761.111.
- Modeling human cortical development in vitro using induced pluripotent stem cellsMariani J, Simonini MV, Palejev D, Tomasini L, Coppola G, Szekely AM, Horvath TL, Vaccarino FM. Modeling human cortical development in vitro using induced pluripotent stem cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 12770-12775. PMID: 22761314, PMCID: PMC3411972, DOI: 10.1073/pnas.1202944109.
- Pooled Short Hairpin (shRNA) Library Screen Coupled with Next-Generation Sequencing Efficiently Uncover Transcriptional Network in Neural Lineage Development of Human Embryonic Stem Cells (IN8-1.009)Szekely A, Zhang Y, Reed B, Schulz V, Wang Z, Euskirchen G, Snyder M, Ivanova N, Weissman S. Pooled Short Hairpin (shRNA) Library Screen Coupled with Next-Generation Sequencing Efficiently Uncover Transcriptional Network in Neural Lineage Development of Human Embryonic Stem Cells (IN8-1.009). Neurology 2012, 78: in8-1.009-in8-1.009. DOI: 10.1212/wnl.78.1_meetingabstracts.in8-1.009.
- Pooled Short Hairpin (shRNA) Library Screen Coupled with Next-Generation Sequencing Efficiently Uncover Transcriptional Network in Neural Lineage Development of Human Embryonic Stem Cells (P02.016)Szekely A, Zhang Y, Reed B, Schulz V, Wang Z, Euskirchen G, Snyder M, Ivanova N, Weissman S. Pooled Short Hairpin (shRNA) Library Screen Coupled with Next-Generation Sequencing Efficiently Uncover Transcriptional Network in Neural Lineage Development of Human Embryonic Stem Cells (P02.016). Neurology 2012, 78: p02.016-p02.016. DOI: 10.1212/wnl.78.1_meetingabstracts.p02.016.
- Induced pluripotent stem cells: A new tool to confront the challenge of neuropsychiatric disordersVaccarino FM, Stevens HE, Kocabas A, Palejev D, Szekely A, Grigorenko EL, Weissman S. Induced pluripotent stem cells: A new tool to confront the challenge of neuropsychiatric disorders. Neuropharmacology 2011, 60: 1355-1363. PMID: 21371482, PMCID: PMC3087494, DOI: 10.1016/j.neuropharm.2011.02.021.
- Annual Research Review: The promise of stem cell research for neuropsychiatric disordersVaccarino FM, Urban AE, Stevens HE, Szekely A, Abyzov A, Grigorenko EL, Gerstein M, Weissman S. Annual Research Review: The promise of stem cell research for neuropsychiatric disorders. Journal Of Child Psychology And Psychiatry 2011, 52: 504-516. PMID: 21204834, PMCID: PMC3124336, DOI: 10.1111/j.1469-7610.2010.02348.x.
- Dynamic transcriptomes during neural differentiation of human embryonic stem cells revealed by short, long, and paired-end sequencingWu JQ, Habegger L, Noisa P, Szekely A, Qiu C, Hutchison S, Raha D, Egholm M, Lin H, Weissman S, Cui W, Gerstein M, Snyder M. Dynamic transcriptomes during neural differentiation of human embryonic stem cells revealed by short, long, and paired-end sequencing. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 5254-5259. PMID: 20194744, PMCID: PMC2841935, DOI: 10.1073/pnas.0914114107.
- Genome-Wide Occupancy of SREBP1 and Its Partners NFY and SP1 Reveals Novel Functional Roles and Combinatorial Regulation of Distinct Classes of GenesReed BD, Charos AE, Szekely AM, Weissman SM, Snyder M. Genome-Wide Occupancy of SREBP1 and Its Partners NFY and SP1 Reveals Novel Functional Roles and Combinatorial Regulation of Distinct Classes of Genes. PLOS Genetics 2008, 4: e1000133. PMID: 18654640, PMCID: PMC2478640, DOI: 10.1371/journal.pgen.1000133.
- Karyotype–phenotype insights from 11q14.1‐q23.2 interstitial deletions: FZD4 haploinsufficiency and exudative vitreoretinopathy in a patient with a complex chromosome rearrangementLi P, Zhang HZ, Huff S, Nimmakayalu M, Qumsiyeh M, Yu J, Szekely A, Xu T, Pober BR. Karyotype–phenotype insights from 11q14.1‐q23.2 interstitial deletions: FZD4 haploinsufficiency and exudative vitreoretinopathy in a patient with a complex chromosome rearrangement. American Journal Of Medical Genetics Part A 2006, 140A: 2721-2729. PMID: 17103440, DOI: 10.1002/ajmg.a.31498.
- Werner Protein Protects Nonproliferating Cells from Oxidative DNA DamageSzekely AM, Bleichert F, Nümann A, Van Komen S, Manasanch E, Nasr A, Canaan A, Weissman SM. Werner Protein Protects Nonproliferating Cells from Oxidative DNA Damage. Molecular And Cellular Biology 2005, 25: 10492-10506. PMID: 16287861, PMCID: PMC1291253, DOI: 10.1128/mcb.25.23.10492-10506.2005.
- Werner protein recruits DNA polymerase δ to the nucleolusSzekely A, Chen Y, Zhang C, Oshima J, Weissman S. Werner protein recruits DNA polymerase δ to the nucleolus. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 11365-11370. PMID: 11027336, PMCID: PMC17206, DOI: 10.1073/pnas.97.21.11365.