A-to-I RNA editing in the CNS
Peripheral immune markers and mechanisms
Welcome to the Breen Lab
Our research is at the intersection of functional genomics, computational biology and neuroscience. Our lab aims to gain more nuanced and accurate insights into the epigenomic/epitranscriptomic mechanisms that underlie brain development and neurodevelopmental disorders, including rare monogenic disorders. We generate genome-wide transcriptomic, proteomic, ChIP/CLIP-sequencing data from a combination of hiPSC models and postmortem brain tissues and analyze these data under a prism of computational methods and tools. Our ultimate goal is to advance discovery of high-value therapeutic targets, biomarkers and mechanisms that contribute to brain development and disease for subsequent functional and clinical validation.
RESEARCH TOPICS: epigenomics, epitranscriptomics, neurodevelopment, hiPSCs, autism spectrum disorder, rare monogenic disorders, schizophrenia, antisense oligonucleotides, scRNA-seq, proteomics, adenosine-to-inosine (A-to-I) editing.
Michael S. Breen, PhD (he/him)
I study brain development and neurodevelopmental disorders utilizing functional genomic techniques. I am an advocate for all things RNA (and DNA). In 2008, I joined the Center of Genomic Regulation (Barcelona, ES) as a Scientist where I developed statistical methods to measure epistatic interactions and their influence on complex traits. Later, I received a PhD in Genomics and Bioinformatics from the University of Southampton (Southampton, UK). My thesis work examined immunological, epigenetic and transcriptomic mechanisms underlying a range of major neuropsychiatric disorders. In 2016, I started postdoctoral training in Molecular Psychiatry and Genomics at the Icahn School of Medicine at Mount Sinai. In 2019, I joined the Faculty at the Icahn School of Medicine at Mount Sinai as Assistant Professor and started the Neuropsychiatric Functional Genomics Laboratory.
Depts. Psychiatry, Genetics and Genomic Sciences
ICAHN BUILDING 14-26
Icahn School of Medicine at Mount Sinai
1425 Madison Avenue, Box 1498
New York, NY 10029
Contact: xuanjia.fan [at] mssm.edu
Sinja completed his undergraduate student at Johns Hopkins University where he studied Medicine, Science, and the Humanities as well as Economics. He has been working in the lab since the summer of 2018 and performs genomic research of autism in blood and brain cells. His work consists heavily on computational biology, bioinformatics and programming using the R statistical language. He has created several data sharing websites and R Shiny apps and has analyzed numerous single cell RNA sequencing datasets. His goals are to continue conducting research with single cell RNA sequencing projects after his graduation and to enter medical school to attain an M.D. in the distant future.
Contact: xkmoore2 [at] scu.edu
Kendall is in her senior year at Santa Clara University where she is studying Neuroscience and Ethnic Studies and does interdisciplinary research on anti-bias virtual reality technology. She joined the lab in 2021 as a SURP(summer undergraduate research program) student and is working on RNA binding proteins as trans regulators of RNA editing activity in the human brain and across development. Kendall hopes in her future to pursue a career centering her passion for inclusive science and healthcare.
- Enrico Mossotto, PhD was a postdoctoral fellow and is now leading genomic research in Industry
A-to-I RNA editing in the brain
Adenosine to inosine (A-to-I) editing is the most common form of RNA editing, affecting the majority of human genes and is highly prevalent in the brain. These base-specific changes to RNA result from site-specific deamination of nucleotides catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes, whereby a genetically encoded adenosine is edited into an inosine, which is read by the cellular machinery as a guanosine. Editing sites in coding regions can be conserved across species and are commonly located in genes involved in neuronal function. Mechanisms of RNA editing are known to modulate excitatory responses, permeability of ion channels and other neuronal signaling functions. These sites also have been shown to be tightly and dynamically regulated throughout pre- and post-natal human cortical development. To these ends, it is perhaps unsurprising that aberrant RNA editing is also implicated in several neurological disorders, including schizophrenia (see here), autism spectrum disorder, major depression, Alzheimer’s disease, and amyotrophic lateral sclerosis.
We are focused on three central areas:
- First, we aim to uncover novel RNA editing sites implicated in mood disorders and neurodevelopmental disorders using large-scale RNA-sequencing and single-cell RNA-sequencing data from postmortem brain tissue and neuronal cell systems.
- Second, we seek to examine the functional impact of these RNA editing sites on protein function and phenotype, and we are specifically focused on sites encoding glutamatergic receptors, ion channels and pumps.
- Third, we aim to develop site-directed RNA editing approaches for therapeutic correction of candidate RNA editing sites as well as highly penetrant, rare mutations.
The immune system and psychiatric disease: biomarkers and treatments
There is substantial clinical and biological evidence for associations between psychiatric disorders and altered immune function, including changes in proinflammatory cytokines IL-1β, IL-6 and TNFα (see here). These molecules have unique and specific actions on immune system function and on neurons and circuits within the central nervous system, including impacts on glucocorticoid function and neurotransmission. Our research has supported and extended these hypotheses by establishing clear associations between proinflamatory cytokine gene networks with trauma and anxiety-related disorders, including posttraumatic stress disorder and depression (see here and here). Our lab is focused on: (1) Integrating scRNA-sequencing and novel in vitro assays to develop accurate and scalable blood-based diagnostics for trauma and anxiety-related disorders; (2) the trans-generational effects of maternal anxiety on early childhood health and development, specifically in low and middle income settings (see here); (3) immune markers and mechanisms in children with idopathic and syndromic forms of autism.
We are also interested in solving emerging biological and algorithmic problems, which arise from our studies and others, such as: a) comparative transcriptomics and proteomics; b) modelling transgenerational effects across generations; c) predicting cellular frequencies from heterogeneous biological tissue; d) multi-modal integrative deep machine-learning applications; e) modelling RNA-editing in from heterogeneous RNA-sequencing data; f) gene network reconstruction and multi-modal omic data integrations. In addition to generating new data in support of these aims, we also use just about any high-throughput data we get our hands on in the public domain, which can ultimately be translated into better understanding biology.
Check some of our Rshiny apps:
The Seaver Autism Center for Research and Treatment
Our laboratory is part of the Seaver Autism Center for Research and Treatment. The Seaver Center is comprised of a diverse, yet complimentary group of scientists, including neuroscientists, molecular biologists, statisticians, clinicians, and stem cell investigators. Researchers in the center work to increase knowledge about the symptoms, biology, and treatment of autism spectrum disorder (ASD).
As a part of the Seaver Center, our lab is primarily focused on understanding the immunobiological mechanisms associated with rare monogenic subtypes of ASD, including Phelan McDermid-Syndrome (PMS; SHANK3), ADNP syndrome, and FOXP1 syndrome. We also collaborate with groups in the Center that generate genetically modified animal models for these genes as well as human iPSC-derived neurons, which we profile using functional genomic tools. To learn more about the Seaver Center, please visit: https://icahn.mssm.edu/research/seaver
Follow the Seaver Autism Center on Twitter:
Breen MS, Garg P, Tang L, Mendonca D, Levy T, Barbosa M, Arnett AB, Kurtz-Nelson E, Agolini E, Battaglia A, Chiocchetti AG. Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype. The American Journal of Human Genetics. (2020).
Breen MS, Browne A, Hoffman GE, Stathopoulos S, Brennand K, Buxbaum JD, Drapeau E. Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism. Molecular autism. (2020).
- Statterstrom KF, Kosmicki JA, Wang J, Breen MS, De Rubeis S, Joon A et al., Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. Cell. (2020)
- Breen MS*, Dobbyn A, Li Q, Roussos P, Hoffman GE, Stahl E et al., Global landscape and genetic regulation of RNA editing in cortical samples from individuals with schizophrenia. Nature Neuroscience. (2019).
- Breen MS*, Bierer L, Bader HN, Makotkine I, Chattopadhyay M et al., Differential transcriptional response to glucocorticoid activation in cultured blood immune cells: a novel approach to PTSD biomarker development. Translational Psychiatry. (2019) .
- Wingo AP, Dammer E, Breen MS, Logsdon BA, Duong DM, Yang J, Troncosco JC et al., Large-scale proteomic analysis of human prefrontal cortex identifies proteins associated with cognitive trajectory in advanced age.Nature Communications (2019). Apr 8. DOI:10.1038/s41467-019-09613-z. PMID:30962425
- Breen MS*, Ozcan S, Ramsey J, Rustogi N, Gottschalk M, Webster M et al., Temporal proteomic profiling of postnatal human cortical development. Translational Psychiatry (2018). Dec 5; 8(1):267. DOI:1038/s41398-018-0306-4. PMID: 30518843.
- Breen MS*, Wingo AP, Koen N, Donald K, Zar HJ, Ressler KJ et al., Gene expression in cord blood links genetic risk for neurodevelopmental disorders with prenatal maternal distress and adverse childhood outcomes. Brain, Behavior, and Immunity (2018). May 20. DOI: 10.1016/j.bbi.2018.05.016. PMID: 29791872.
- Breen MS*, Tylee D, Maihofer A, Neylan T, Mehta D, Binder E et al., PTSD blood transcriptome mega-analysis: Shared inflammatory pathways across biological sex and modes of trauma. Neuropsychopharmacology(2017). Sep 19. DOI:10.1038/npp.2017.220. PMID: 28925389.
- Breen MS*, White CH, Shekhtman T, Lin K, Looney D, Woelk CH, Kelsoe JR. Identification of lithium responsive genes and gene networks in bipolar disorder patient derived lymphoblastoid cell lines.Pharmacogenomics Journal (2016). Oct; 16(5): 446-53. DOI:10.1038/tpj.2016.50. PMID: 27401222.
- Breen MS*, Maihofer A, Glatt ST, Chandler SD, Tsuang M, Risbrough V et al., Gene networks specific for innate immunity define post-traumatic stress disorder. Molecular Psychiatry (2015). Dec; 20(12):1538-45. DOI: 10.1038/mp.2015.9. PMID: 25754082.
- Breen MS, Kemena C, Vlasov P, Notredame C, Kondrashov, F. Epistasis as the primary factor in molecular evolution. Nature (2012). Oct; 490(7421): 535-8. DOI:10.1038/nature11510. PMID: 23064225.
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• Complete curriculum vitae, including a list of publications.
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