A-to-I RNA editing in the CNS
Rare developmental disorders and RNA therapeutics
Laboratory of A-to-I RNA editing and rare neurodevelopment disorders
Our research is dedicated to RNA editing and genetics/genomics of neurological disorders. We are especially passionate about rare neurodevelopment disorders. We combine methodologies across human neurogenetics, computational biology, molecular biology, and cellular neuroscience. We have three main research foci:
1. We pioneer state of the art genomic investigations of monogenic neurodevelopment disorders.
2. We develop oligonucleotide-directed RNA editing therapeutics to treat these disorders.
3. We leverage large-scale transcriptomics to dissect RNA editing function and regulation in brain development, disease and aging.
LAB CULTURE AND PHILOSOPHY: In our lab, we prioritize and promote a healthy work/life balance as well as a positive, promotional, inclusive, respectful and productive lab culture. My primary focus as a mentor is to train, motivate and inspire the next-generation of academic and industry scientists – everyone’s journey is different! Ultimately, my ambition is for each member to make a positive scientific impact and to grow professionally through rigorous, ethical and highly original science and outreach. We work as part of a diverse cross-functional team of computational and experimental biologists. We also function as part of a highly collaborative environment in the Seaver Autism Center for Research and Treatment at Mount Sinai, the MINDICH Child Health and Development Institute and the Depts. of Genetics and Genomic Sciences and Psychiatry.
RESEARCH TOPICS: adenosine-to-inosine editing, mRNA secondary structure, brain development, autism spectrum disorder and syndromic subtypes, schizophrenia, neurodegeneration, aging, immunogenetics of developmental disorders, human genetics, gene and protein expression, 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.
Michael S. Breen, PhD (he/him)
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.
Contact: olga.dmitrichenko [@] mssm.edu
As a health scientist and epidemiologist, Olga’s work focuses on suboptimal pregnancy and neurodevelopmental aspects during childhood, linked with neuroimaging. She has worked on the Generation R Cohort at the Erasmus Medical Center in Rotterdam, the Netherlands, and conducted research on eating behaviours in association with brain morphology in children. After joining Icahn School of Medicine at Mount Sinai, her work focuses on maternal immune activation and brain outcomes, where she is also part of the Women’s Mental Health Program. Outside research, she enjoys long walks with friends and art expositions.
- Xuanjia (Sinja) Fan was a Associate Researcher/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.
- Gauri Ganesh was a MSc student and is now a bioinformatician in industry.
- Ariela Buxbaum Grice was an Associate Researcher and is now a PhD graduate student.
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:
- 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.
- 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.
- 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 (see here) and Phelan McDermid Syndrome (see here).
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
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 lab publications
- Spatiotemporal and genetic regulation of A-to-I editing throughout human brain development. Cell Reports. (2022).
- Cellular and genetic drivers of RNA editing variability in the human brain. Nature Communications. (2022)
- Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression. Nature Neuroscience. (2022)
Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype. The American Journal of Human Genetics. (2020).
- Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. Cell. (2020)
- Global landscape and genetic regulation of RNA editing in cortical samples from individuals with schizophrenia. Nature Neuroscience. (2019).
- Differential transcriptional response to glucocorticoid activation in cultured blood immune cells: a novel approach to PTSD biomarker development. Translational Psychiatry. (2019) .
- Large-scale proteomic analysis of human prefrontal cortex identifies proteins associated with cognitive trajectory in advanced age.Nature Communications (2019).
- Temporal proteomic profiling of postnatal human cortical development. Translational Psychiatry (2018).
- Gene expression in cord blood links genetic risk for neurodevelopmental disorders with prenatal maternal distress and adverse childhood outcomes. Brain, Behavior, and Immunity (2018).
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 firstname.lastname@example.org
• Complete curriculum vitae, including a list of publications.
• A very brief summary of current work and research interests.
• Contact information for two references.
Contact: Depts. Psychiatry, Genetics and Genomic Sciences
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