Breen Laboratory

Functional genomics applied to neurodevelopmental disorders

A-to-I RNA editing in the CNS

Immunogenetics of rare developmental disorders

Welcome to the Breen Lab!

Our research is at the intersection of functional genomics, computational biology and neuroscience. Our lab dissects the cellular and molecular mechanisms that drive brain development and their dysfunction in neurodevelopmental disorders. We also study the immunogenetics of rare developmental disorders. We are especially focused on mechanisms related to post-transcriptional RNA modifications (A-to-I RNA editing), alternative splicing, gene expression, and protein interactions/networks, as well as the genetic drivers of this variability. We generate multimodal genomic data from hiPSC neuronal models, postmortem brain tissues, and peripheral blood samples, 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: brain development, autism spectrum disorder and syndromic subtypes, schizophrenia, neurodegeneration, immunogenetics of developmental disorders, human genetics, gene and protein expression, adenosine-to-inosine editing, mRNA secondary structure, alternative splicing, quantitative trait loci.

GENOMIC TECHNOLOGIES AND METHODS: WGS, WES, DNAm arrays, transcriptomics (single-cell RNA-seq, RNA-seq, long read isoform-sequencing), mass spectrometry proteomics and metabolomics, multi ‘omic’ computational models and tools, CRISPRi, fluorescence activated cell and nuclei sorting, cytometry time of flight, neuronal culturing, antisense oligonucleotides, hiPSC-derived neurons and neuronal model systems.
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Michael S. Breen, PhD (he/him)
Assistant Professor
I am the Principal Investigator of a terrific team specializing in human genetics and genomics, computational biology and cellular neuroscience. In 2008, I joined the Center of Genomic Regulation (Barcelona, Spain) 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 (United Kingdom) investigating 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 Breen Lab in the Departments of Psychiatry and Genetics and Genomic Sciences. Our lab is also a proud member of the Seaver Autism Center for Research and Treatment.

 

 

 

 

 

 

Miguel Rodriguez de los Santos, PhD (he/him)
Postdoctoral fellow
Contact: miguel.rodriguezdls [at] mssm.edu
 
 
 
 
 
 
Winston H. Cuddleston, MSc (he/they)
Graduate student
Contact: ryn.cuddleston [at] icahn.mssm.edu
Winston completed their undergraduate education at the University of Nevada, Reno where they majored in Neuroscience with a minor in Biochemistry. They went on to earn a Master’s in Cellular and Molecular Biology also from UNR where they researched post-transcriptional gene regulatory mechanisms, namely alternative splicing and alternative polyadenylation in the central nervous system. In 2020, Winston joined as a PhD student in the Biomedical Sciences graduate program through the Genomics and Data Science multidisciplinary training area. They are currently mapping cell- and isoform-specific A-to-I editing in the brain. Outside of research, Winston is passionate about science communication and promoting the success and wellbeing of students/trainees belonging to groups underrepresented in science.
 
 
 
Gauri Ganesh
Biomedical Sciences Master’s Student
Contact: gauri.ganesh [@] icahn.mssm.edu

Gauri is a first year Biomedical Sciences Master’s Student at the Icahn School of Medicine at Mount Sinai. She graduated from UCLA in 2018 with degrees in Molecular, Cell, and Developmental Biology and Neuroscience. After spending a few post-graduate years working in industry and academia, she returned to school to explore her interests in neurodegenerative and rare diseases. She joined the Breen Lab in November 2021, and is currently researching RNA hyper-editing events in Alzheimer’s disease. In the future, Gauri hopes to either further her graduate education through a PhD program or work in industry.

 

Ariela Buxbaum Grice (she/her)
Research Associate
Contact: ariela.buxbaumgrice [@] mssm.edu

Ariela graduated from Connecticut College in 2020 with a major in Biological Sciences and a minor in Studio Art. She joined the Breen lab team in October of 2021 and is currently using scRNA-seq approaches to explore cell type-specific differences in gene expression profiles associated with rare syndromic subtypes of autism spectrum disorder. In the future, she aims to attend graduate school and continue research on the -omics of neurological/neurodevelopmental disorders.

 

 

 
Lab Alumni:
  • Xuanjia (Sinja) Fan was a Research Assistant/Lab Manager and is now attending Medical School at Penn State.
  • Enrico Mossotto was a postdoctoral fellow and is now leading genomic research in Industry
  • Joshua Senior was a research volunteer from Brooklyn Technical High School and is now attending University.
  • Kendall Moore was a SURP student and is currently finishing studies at Santa Clara University studying Neuroscience and Ethnic Studies.
  • Sarah Zipkowitz was a Research Volunteer and is currently attending Binghamton University where she is studying Biology and Judaic Studies on the Pre-Med track.

Our Research

 

Genomics of brain development and neurodevelopmental disorders

Our work pioneers large-scale genomic investigations of human cortical developmental, combing genetics, transcriptomics and proteomics (see here and here). These studies chart the complex spatiotemporal and genetic regulation of gene expression and protein abundance, their functions and timely interactions across fetal and postnatal development. We have also led studies dissecting post-transcriptional A-to-I modifications and their roles in supporting the functional diversity of human brain development (see here). In addition, our lab is part of the Autism Sequencing Consortiums (ASC), dedicated to dissecting the genetic architecture of ASD through large-scale whole exome sequencing and de novo variant discovery (see here). We are also part of the Seaver Autism Center for Research and Treatment at Mount Sinai, where we led a number of studies focused on rare monogenic subtypes of autism (see here a report of transcriptional alterations in hiPSC-derived neurons as a consequence of 22q13.3 sequence variants and deletions in participants with Phelan-McDermid syndrome).

 

Mapping the regulation and function of A-to-I editing in brain health and disease

Another component of our work is focused on elucidating highly regulated adenosine-to-inosine (A-to-I) editing sites in the human brain both with the main goal to prioritize RNA editing sites for functional, mechanistic, and RNA therapeutic investigation. Currently, we are tackling aspects of RNA editing regulation across brain development (see here), major brain cell types and their genetic regulation (see here) and dysregulation in neurological disorders (see our work in schizophrenia here). We are focused on three central areas:

  1. First, we aim to uncover A-to-I sites implicated in neurodevelopmental and neurodegenerative disorders using large-scale RNA-seq and snRNA-seq from postmortem brain samples and neuronal cell systems.
  2. Second, we seek to examine the functional impact of these RNA editing sites on protein function and cellular phenotypes, and we are specifically focused on sites encoding glutamatergic receptors, ion channels and pumps.
  3. Third, we aim to develop site-directed RNA editing approaches for therapeutic correction of disease-related RNA editing sites as well as therapeutic repair of highly penetrant, rare genomic point mutations at the mRNA level.

 

Immuno-genetics of neurodevelopmental disorders: biomarkers and treatments

We have investigated the immunobiology of major neurological disorders for the past 10 years (see a few examples here, here, here, here). In the Seaver Autism Center, we are leveraging this expertise to dissect the immunogenetics and immunobiology of children with rare developmental disorders. Our research in the Center surveys peripheral immune responsivity and function in children with rare syndromic subtypes of autism using high-throughput genomic and cellular techniques, including scRNA-seq, metabolomics, proteomics and cytometry by time of flight. This work has uncovered novel immunodeficiencies that underlie recurrent infections in rare disorders that are typically studied in the context of the central nervous system, thereby providing avenues for biomarker development and new therapeutic interventions to tackle common immune-related phenotypes. Our work has also described novel molecularly defined genetic subtypes in both ADNP syndrome and Phelan McDermid Syndrome (see here).

Algorithm Development

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:
  • Temporal proteomic profiling across postnatal cortical development (see here)
  • Transcriptional response to glucocorticoid stimulations in PBMCs from warfighters (see here)
  • Cell type specific transcriptome profiling in umbilical cord blood (see here)
  • The Seaver scRNA-seq Resource (see here)

The Seaver Autism Center for Research and Treatment

The Breen Lab is part of the Seaver Autism Center for Research and Treatment at the Icahn School of Medicine at Mount Sinai. The Seaver Autism Center is a fully integrated, translational research center that leads progressive studies and provides personalized care to individuals with autism and related rare disorders. As a team, we are dedicated to discovering the biological causes of autism and developing breakthrough treatments.

As a part of the Seaver Center, our lab is primarily focused on understanding the cellular and molecular consequences underlying rare syndromic forms of autism, including Phelan McDermid-Syndrome (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. Learn more about the Seaver Center here: https://icahn.mssm.edu/research/seaver

Follow the Seaver Autism Center on Twitter:

Select publications

*corresponding author
  • 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.

Available Positions

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. If you are interested in applying for a position, please send the following information to michael.breen@mssm.edu
• Complete curriculum vitae, including a list of publications.
• A very brief summary of current work and research interests.
• Contact information for two references.

Contact Us

Contact: 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