A5049988366- Single-cell and spatial transcriptomics
- Cell Image Analysis Techniques
- Vestibular and auditory disorders
- Gene Regulatory Network Analysis
- Parkinson's Disease Mechanisms and Treatments
- Amyotrophic Lateral Sclerosis Research
- Hearing, Cochlea, Tinnitus, Genetics
- Neurogenetic and Muscular Disorders Research
- Epigenetics and DNA Methylation
- Neuroinflammation and Neurodegeneration Mechanisms
- Neural dynamics and brain function
- Gene expression and cancer classification
- Biomedical Text Mining and Ontologies
- RNA Research and Splicing
- Prion Diseases and Protein Misfolding
- Olfactory and Sensory Function Studies
- Genetics and Neurodevelopmental Disorders
- Molecular Biology Techniques and Applications
- Medicinal Plant Pharmacodynamics Research
- Congenital heart defects research
- Genomics and Rare Diseases
- MicroRNA in disease regulation
- Nuclear Receptors and Signaling
- Advanced Fluorescence Microscopy Techniques
- 3D Printing in Biomedical Research
Massachusetts Institute of Technology
2023-2024
Broad Institute
2018-2024
IIT@MIT
2022
Stanley Center for Psychiatric Research
2018-2022
Abstract The cerebellar cortex is a well-studied brain structure with diverse roles in motor learning, coordination, cognition and autonomic regulation. However, complete inventory of cell types currently lacking. Here, using recent advances high-throughput transcriptional profiling 1–3 , we molecularly define across individual lobules the adult mouse cerebellum. Purkinje neurons showed considerable regional specialization, greatest diversity occurring posterior lobules. For several...
Abstract The clinical presentation of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, varies widely across patients, making it challenging to determine if potential therapeutics slow progression. We sought whether there were common patterns disease progression that could aid in the design and analysis trials. developed an approach based on mixture Gaussian processes identify clusters patients sharing similar patterns, modeling their average trajectories variability...
Abstract Several prior studies have proposed the involvement of various brain regions and cell types in Parkinson’s disease (PD) pathology. Here, we performed snRNA-seq on prefrontal cortex anterior cingulate from a small cohort post-mortem control PD tissue. We found significant association oligodendrocytes (ODCs) oligodendrocyte precursor cells (OPCs) with PD-linked risk loci report several dysregulated genes pathways, including regulation tau-protein kinase activity, inclusion body...
The cerebellum is a well-studied brain structure with diverse roles in motor learning, coordination, cognition, and autonomic regulation. Nonetheless, complete inventory of cerebellar cell types presently lacking. We used high-throughput transcriptional profiling to molecularly define across individual lobules the adult mouse cerebellum. Purkinje granule neurons showed considerable regional specialization, greatest diversity occurring posterior lobules. For multiple interneurons, molecular...
Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured ATAC-seq, motor neuron cultures derived from diverse group 380 ALS patients and 80 healthy controls. We find that chromatin accessibility heavily influenced sex, the iPSC cell type origin, ancestry, inherent variance arising sequencing....
Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neuron (MN) loss. We previously discovered that macrophage migration inhibitory factor (MIF), whose levels are extremely low spinal MNs, inhibits mutant misfolding and toxicity. In this study, we show single peripheral injection of adeno-associated virus (AAV) delivering MIF into adult SOD1G37R mice significantly improves their function, delays progression, extends survival....
Summary Defining cell types requires integrating diverse measurements from multiple experiments and biological contexts. Recent technological developments in single-cell analysis have enabled high-throughput profiling of gene expression, epigenetic regulation, spatial relationships amongst cells complex tissues, but computational approaches that deliver a sensitive specific joint these datasets are lacking. We developed LIGER, an algorithm delineates shared dataset-specific features...
Abstract A key aspect of nearly all single cell experiments is the necessity to dissociate intact tissues into suspensions for processing. While many protocols have been optimized optimal yield, they often overlooked effects that dissociation can on ex vivo gene expression changes during this process. Microglia, brain’s resident macrophages, are a highly dynamic population extremely sensitive their microenvironment and shown dramatically alter transcriptome upon stimulation. We demonstrate...
Several prior studies have proposed the involvement of various brain regions and cell types in Parkinson's disease (PD) pathology. Here, we performed snRNA-seq on prefrontal cortex anterior cingulate from post-mortem control PD tissue. We found a significant association oligodendrocytes (ODCs) oligodendrocyte precursor cells (OPCs) with PD-linked risk loci report several dysregulated genes pathways, including regulation tau-protein kinase activity, inclusion body assembly protein processing...
Abstract High-throughput single-cell sequencing technologies hold tremendous potential for defining cell types in an unbiased fashion using gene expression and epigenomic state. A key challenge realizing this is integrating datasets from multiple protocols, biological contexts, data modalities into a joint definition of cellular identity. We previously developed approach called Linked Inference Genomic Experimental Relationships (LIGER) that uses integrative nonnegative matrix factorization...
Detection of copy number variants (CNVs) is an important aspect clinical testing for several disorders, including Duchenne muscular dystrophy, and often performed using multiplex ligation-dependent probe amplification (MLPA). However, since many genetic carrier screens depend instead on next-generation sequencing (NGS) wider discovery small variants, they do not include CNV analysis. Moreover, most computational techniques developed to detect CNVs from exome data are suitable screening, as...
Abstract To understand how the cerebellar cortex transforms mossy fiber (MF) inputs into Purkinje cell (PC) outputs, it is vital to delineate elements of this circuit. Candelabrum cells (CCs) are enigmatic interneurons that have been identified based on their morphology, but electrophysiological properties, synaptic connections, and function remain unknown. Here we clarify these properties using electrophysiology, snRNA sequencing, in situ hybridization, serial electron microscopy. We find...
Abstract Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured ATAC-seq, motor neuron cultures derived from diverse group 380 ALS patients and 80 healthy controls. We find that chromatin accessibility heavily influenced sex, the iPSC cell type origin, ancestry, inherent variance arising...