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. We use transcriptomic, proteomic, ChIP/CLIP-sequencing approaches to investigate gene expression, RNA editing and protein function in neurodevelopmental and neuropsychiatric disorders. We focus on two mechanistic-domains: 1) A-to-I RNA editing in the brain, which drives neurodevelopment by expanding the functional output for the majority of human neuronal genes; and 2) immune mechanisms in the blood, which offer alternative avenues for biomarker development and treatments. We generate genomic data sets from patient tissues (e.g. peripheral blood, cord blood, postmortem brain tissue, hiPSCs) and analyze these data under a prism of biostatistical methods. In doing so, we strive to construct biologically plausible mechanistic models of disease that we validate both functionally and clinically. Ultimately, our work aims to advance the development of treatments for serious mental disorders and to improve the quality of life.
RESEARCH TOPICS: Big data analytics in neuroscience, RNA editing, transcriptomics, single-cell RNA-sequencing, long read sequencing, proteomics, brain development, autism, schizophrenia, PTSD, biomarker development, clinical trials.
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 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.
- 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.
We strive to maintain an open-minded, creative and productive research environment, and we are fully committed to foster the growth and development of trainees in the wet and dry labs.
Postdoctoral Fellow in RNA Editing [experimental biology]
We are seeking an ambitious, creative, and motivated Postdoctoral Fellow with expertise in molecular and neurobiology to study the therapeutic effects of site-directed RNA editing to repair rare genomic mutations that cause neurodevelopmental disorders. The position requires a molecular background and experience with neuronal cell culture, immunostaining, molecular cloning and transient transfections, plasmid construction and/or AAV vector and virus preparations.
The Postdoctoral Fellow will be responsible for:
- Establish a platform for repairing high penetrant rare genetic variants at the RNA level using site directed RNA editing (SDRE) as part of the mutations being studied in the Seaver Autism Center.
- Development of chemically optimized antisense oligonucleotides that recruit endogenous editing enzymes.
- Neuronal cell culturing, immunostaining, working with Cas9 expressing cell lines, building out transient transfection protocols.
- Assume a major role in the writing of scientific publications, fellowships and grant applications and supervise PhD and MSc students.
- Train in basic principles of computational biology to analyze aspects of their own data
Postdoctoral Fellow / Bioinformatician / Computational Biologist
We are seeking an ambitious, creative, and motivated individual with expertise in computational biology to study mechanisms of RNA editing across neurodevelopmental and neuropsychiatric disorders. The position requires a quantitative statistical background and extensive experience with bioinformatics, genetics, genome data analysis and/or neuroscience. The ideal candidate will have strong biological and statistical background with proven expertise in transcriptomics, including RNA-sequencing, long-read isoform-sequencing, and/or single-cell RNA-sequencing. We are open to hiring at all levels for this position.
The individual will be responsible for:
- Computational investigation of large-scale RNA-sequencing, long-read isoform-sequencing, and single-cell RNA-sequencing data to uncover disease- and developmental-specific RNA editing events.
- Establish methods/pipelines to integrate genotypic, RNA editing, splicing and gene expression and proteomic data in health and disease.
- Lead data analysis efforts as a part of large international consortia.
- Assist in studies applying site-directed RNA editing approaches as therapeutic agents to correct rare mutations that are currently being studied in the Seaver Autism Center for Research and Treatment.
- Assume a major role in the writing of scientific publications, fellowships and grant applications and supervise PhD and MSc students.
Please send the following information to email@example.com
• Complete curriculum vitae, including a list of publications.
• A very brief summary of current work and research interests.
• Contact information for two references.
Seaver and Neurogenomics Cyber Seminar Series
We host weekly Cyber Seminar Series featuring internal work in progress and external speakers presenting exciting recent publications and emerging bodies of work. Each presentation is recorded and hosted here for two weeks after the presentation date. A big thank you to all of our presenters!
Hanging Liu and Jingtain Zhou | Salk Institute
“DNA methylation Atlas of the Mouse Brain at Single-Cell Resolution”
Matt Lalli, PhD | Postdoctoral Fellow | Washington University
“Connecting rare mutations to common pathways in human neurons with single-cell CRISPR repression”
Donna Werling, PhD | Assistant Professor | UW-Madison
“Developmental and genetic effects on gene expression in the human brain”
John Sinnamon, PhD | Assistant Professor | Vollum Insitiute at Oregon Health and Science University
“Targeted editing of Mecp2 RNA in a mouse model of Rett Syndrome”
Juan Diaz, PhD | Research Scientist | Marine Biological Laboratory
“Site directed RNA editing as an alternative molecular therapy”