Skip to main content

Eran Mukamel

Follower

1

Following

1

Public Views

Noel B. Salazar

KU Leuven

Universidad Nacional de Colombia (National University of Colombia)

University of Cologne

University of Toronto

(Benemérita) Universidad Autónoma de Puebla

University of Hawaii at Manoa

Charles University, Prague

Mikail F Lumentut

National Taiwan University

Matthieu M de Wit

Muhlenberg College

George Christodoulides

Université de Mons

Interests

Uploads

Papers by Eran Mukamel

Phase II PsychENCODE Acknowledgment Statement

Spectral Learning of Binomial HMMs for DNA Methylation Data

ArXiv, 2018

Author(s): Zhang, Chicheng; Mukamel, Eran A; Chaudhuri, Kamalika | Abstract: We consider learning... more Author(s): Zhang, Chicheng; Mukamel, Eran A; Chaudhuri, Kamalika | Abstract: We consider learning parameters of Binomial Hidden Markov Models, which may be used to model DNA methylation data. The standard algorithm for the problem is EM, which is computationally expensive for sequences of the scale of the mammalian genome. Recently developed spectral algorithms can learn parameters of latent variable models via tensor decomposition, and are highly efficient for large data. However, these methods have only been applied to categorial HMMs, and the main challenge is how to extend them to Binomial HMMs while still retaining computational efficiency. We address this challenge by introducing a new feature-map based approach that exploits specific properties of Binomial HMMs. We provide theoretical performance guarantees for our algorithm and evaluate it on real DNA methylation data.

Sharp : Statistical analysis of super-resolution and hyperacuity from microscopes to retinas

Decision letter: Subcellular sequencing of single neurons reveals the dendritic transcriptome of GABAergic interneurons

eLife, 2020

Although mRNAs are localized in the processes of excitatory neurons, it is still unclear whether ... more Although mRNAs are localized in the processes of excitatory neurons, it is still unclear whether interneurons also localize a large population of mRNAs. In addition, the variability in the localized mRNA population within and between cell types is unknown. Here we describe the unbiased transcriptomic characterization of the subcellular compartments of hundreds of single neurons. We separately profiled the dendritic and somatic transcriptomes of individual rat hippocampal neurons and investigated mRNA abundances in the soma and dendrites of single glutamatergic and GABAergic neurons. We found that, like their excitatory counterparts, interneurons contain a rich repertoire of~4000 mRNAs. We observed more cell type-specific features among somatic transcriptomes than their associated dendritic transcriptomes. Finally, using celltype-specific metabolic labeling of isolated neurites, we demonstrated that the processes of glutamatergic and, notably, GABAergic neurons were capable of local translation, suggesting mRNA localization and local translation are general properties of neurons.

Thermodynamics and the matter of life

Science, 2020

A scientist considers life's genesis through the physics of Exodus What is life? Seventy-five... more A scientist considers life's genesis through the physics of Exodus What is life? Seventy-five years after Erwin Schrödinger took up this fundamental human question, another physicist, Jeremy England, offers a bold update. His new book, Every Life Is on Fire, explores the physics of what makes some configurations of matter lifelike and others inert.

776. Simultaneous Intra- And Extracranial Recording of Prefrontal Neural Activity in Awake, Behaving Rats

Biological Psychiatry, 2017

Background: Depression is characterized by deficits in cognitive control, including impaired perf... more Background: Depression is characterized by deficits in cognitive control, including impaired performance after errors. Particularly, event-related potential (ERP) studies have shown that these impairments are linked to potentiated responses in paralimbic regions, coupled with reduced recruitment of cognitive control regions (dorsolateral prefrontal cortex). Despite these advances, several gaps remain. First, it is unclear whether such disruptions persist after remission. Second, little is known about whether similar post-error deficits emerge in rodent models relevant to depression. Methods: 128-channel ERPs were recorded while 30 unmedicated individuals with remitted depression (rMDD) and 34 healthy controls performed an Eriksen Flanker task before and after an acute psychosocial stressor. In rats, posterror behavioral adjustments were evaluated during a 5-choice serial reaction time task after treatment with corticotropinreleasing factor (CRF), a peptide capable of inducing depression-like phenotypes in rodents. In a second rat cohort, we tested whether abnormal post-error adjustments could be reversed by treatment with JDTic, a kappa-opioid receptor antagonist that produces antidepressant-like effects. Results: In humans, the acute stressor reduced frontocingulate activation for the rMDDbut not controlgroup, in regions critically implicated in cognitive control. Stress-induced blunting in frontocingulate activation was associated with dysregulated endocrinological (cortisol) and affective responses to the stressor. In rats, CRF significantly degraded post-error accuracy, but this effect was reduced by JDTic. Conclusions: ERP markers indicate that cognitive control deficits persist after remission, pointing to a potential mechanism for increased relapse risk. Highlighting translational potential, abnormal post-error behavioral adjustments could be recapitulated in a rodent model (CRF administration) relevant to depression.

Phase diagram for unzipping DNA with long-range interactions

Physical review. E, Statistical, nonlinear, and soft matter physics, 2002

We present a critique and extension of the mean-field approach to the mechanical pulling transiti... more We present a critique and extension of the mean-field approach to the mechanical pulling transition in bound polymer systems. Our model is motivated by the theoretically and experimentally important examples of adsorbed polymers and double-stranded DNA. We focus on the case in which quenched disorder in the sequence of monomers is unimportant for the statistical mechanics, but we include excluded volume interactions between monomers. Our phase diagram for the critical pulling force shows an interesting reentrant phase at low temperatures which should be observable in both disordered and homogenous polymer systems. We also consider the case of nonequilibrium pulling, in which the external force probes the molecule's local, rather than global structure. The dynamics of the pulling transition in such experiments could illuminate the polymer's loop structure, which depends on the nature of excluded volume interactions.

Dissipationless spin current in anisotropic p-doped semiconductors

Physical Review B, 2004

Recently, dissipationless spin current has been predicted for the p-doped semiconductors with spi... more Recently, dissipationless spin current has been predicted for the p-doped semiconductors with spinorbit coupling. Here we investigate the effect of spherical symmetry breaking on the dissipationless spin current, and obtain values of the intrinsic spin Hall conducitivity for realistic semiconductor band structures with cubic symmetry.

Biophysical modeling and optical imaging tools for studies of cerebellar motor learning

Motor learning is a precious capacity that humans, from toddlers to athletes and concert pianists... more Motor learning is a precious capacity that humans, from toddlers to athletes and concert pianists, rely on to move with coordination and grace. The neural circuit in the cerebellum that helps us learn new movements and adjust our performance of familiar reflexes is remarkable for its quasi-crystalline architecture, which has been conserved at the cellular level across vertebrate species. This thesis develops and applies tools based on biophysical and computational modeling of neural circuits, as well as analysis of data sets from optical ...

Topological Spin Current in Anisotropic p-Doped Semiconductors

Abstract We present a derivation of the dissipationless electric-field induced topological spin-c... more Abstract We present a derivation of the dissipationless electric-field induced topological spin-current in realistic, anisotropic semiconductors, which extends the isotropic model system first described by Murakami, Nagaosa and Zhang. We find a smaller value of the spin conductance in the anisotropic material than would be predicted based on a spherical approximation for the band structure, although the decrease is only 5 to 20% in real materials. This extension of the previous isotropic model shows that the spin-current is a ...

The BRAIN Initiative Cell Census Network Data Ecosystem: A User’s Guide

Characterizing cellular diversity at different levels of biological organization across data moda... more Characterizing cellular diversity at different levels of biological organization across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also required to manipulate cell types in controlled ways, and to understand their variation and vulnerability in brain disorders. TheBRAIN Initiative Cell Census Network (BICCN)is an integrated network of data generating centers, data archives and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain and demonstration of prototypes for human and non-human primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed, and to accessing and using the BICCN data and its extensive resources, including theBRAIN Cell Data Center (BCDC)which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecos...

Dnmt3a knockout in excitatory neurons impairs postnatal synapse maturation and increases the repressive histone modification H3K27me3

eLife

Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive co... more Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive complex 2 (PRC2), are known to regulate neuronal development and function. However, their respective contributions to brain maturation are unknown. We found that conditional loss of the de novo DNA methyltransferase Dnmt3a in mouse excitatory neurons altered expression of synapse-related genes, stunted synapse maturation, and impaired working memory and social interest. At the genomic level, loss of Dnmt3a abolished postnatal accumulation of CG and non-CG DNA methylation, leaving adult neurons with an unmethylated, fetal-like epigenomic pattern at ~222,000 genomic regions. The PRC2-associated histone modification, H3K27me3, increased at many of these sites. Our data support a dynamic interaction between two fundamental modes of epigenetic repression during postnatal maturation of excitatory neurons, which together confer robustness on neuronal regulation.

Robust enhancer-gene regulation identified by single-cell transcriptomes and epigenomes

Integrating single-cell transcriptomes and epigenomes across diverse cell types can link genes wi... more Integrating single-cell transcriptomes and epigenomes across diverse cell types can link genes with the cis-regulatory elements (CREs) that control expression. Gene co-expression across cell types confounds simple correlation-based analysis and results in high false prediction rates. We developed a procedure that controls for co-expression between genes and integrates multiple molecular modalities, and used it to identify >10,000 gene-CRE pairs that contribute to gene expression programs in different cell types in the mouse brain.

A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex

Nature, 2021

Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased sam... more Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain1–3. With the proliferation of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of cell-type organization. Here we generated transcriptomes and epigenomes from more than 500,000 individual cells in the mouse primary motor cortex, a structure that has an evolutionarily conserved role in locomotion. We developed computational and statistical methods to integrate multimodal data and quantitatively validate cell-type reproducibility. The resulting reference atlas—containing over 56 neuronal cell types that are highly replicable across analysis methods, sequencing technologies and modalities—is a comprehensive molecular and genomic account of the diverse neuronal and non-neuronal cell types in the mouse primary motor cortex. The atlas includes a population of excitatory neurons that resemble...

A multimodal cell census and atlas of the mammalian primary motor cortex

ABSTRACTWe report the generation of a multimodal cell census and atlas of the mammalian primary m... more ABSTRACTWe report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal an...

TH72. The Role of Dna (Hydroxy) Methylation in Epigenetic Regulation of Excitatory and Inhibitory Neurons in the Prefrontal Cortex of Patients with Schizophrenia

European Neuropsychopharmacology, 2021

Evolution of cellular diversity in primary motor cortex of human, marmoset monkey, and mouse

The primary motor cortex (M1) is essential for voluntary fine motor control and is functionally c... more The primary motor cortex (M1) is essential for voluntary fine motor control and is functionally conserved across mammals. Using high-throughput transcriptomic and epigenomic profiling of over 450,000 single nuclei in human, marmoset monkey, and mouse, we demonstrate a broadly conserved cellular makeup of this region, whose similarity mirrors evolutionary distance and is consistent between the transcriptome and epigenome. The core conserved molecular identity of neuronal and non-neuronal types allowed the generation of a cross-species consensus cell type classification and inference of conserved cell type properties across species. Despite overall conservation, many species specializations were apparent, including differences in cell type proportions, gene expression, DNA methylation, and chromatin state. Few cell type marker genes were conserved across species, providing a short list of candidate genes and regulatory mechanisms responsible for conserved features of homologous cell t...

Comprehensive analysis of single cell ATAC-seq data with SnapATAC

Nature Communications, 2021

Identification of the cis-regulatory elements controlling cell-type specific gene expression patt... more Identification of the cis-regulatory elements controlling cell-type specific gene expression patterns is essential for understanding the origin of cellular diversity. Conventional assays to map regulatory elements via open chromatin analysis of primary tissues is hindered by sample heterogeneity. Single cell analysis of accessible chromatin (scATAC-seq) can overcome this limitation. However, the high-level noise of each single cell profile and the large volume of data pose unique computational challenges. Here, we introduce SnapATAC, a software package for analyzing scATAC-seq datasets. SnapATAC dissects cellular heterogeneity in an unbiased manner and map the trajectories of cellular states. Using the Nyström method, SnapATAC can process data from up to a million cells. Furthermore, SnapATAC incorporates existing tools into a comprehensive package for analyzing single cell ATAC-seq dataset. As demonstration of its utility, SnapATAC is applied to 55,592 single-nucleus ATAC-seq profi...

Epigenomic Diversity of Cortical Projection Neurons in the Mouse Brain

SummaryNeuronal cell types are classically defined by their molecular properties, anatomy, and fu... more SummaryNeuronal cell types are classically defined by their molecular properties, anatomy, and functions. While recent advances in single-cell genomics have led to high-resolution molecular characterization of cell type diversity in the brain, neuronal cell types are often studied out of the context of their anatomical properties. To better understand the relationship between molecular and anatomical features defining cortical neurons, we combined retrograde labeling with single-nucleus DNA methylation sequencing to link epigenomic properties of cell types to neuronal projections. We examined 11,827 single neocortical neurons from 63 cortico-cortical (CC) and cortico-subcortical long-distance projections. Our results revealed unique epigenetic signatures of projection neurons that correspond to their laminar and regional location and projection patterns. Based on their epigenomes, intra-telencephalic (IT) cells projecting to different cortical targets could be further distinguished,...

Using the Power of Single-Nucleus Epigenomics to Map the Molecular Complexity of the Adult Brain

Biological Psychiatry, 2020

type information, although the data can be noisy and typically are derived from a small number of... more type information, although the data can be noisy and typically are derived from a small number of subjects. Methods: Complementing these approaches, we develop a statistical method to estimate subject-level cell-type-specific (CTS) gene expression by borrowing information across multiple measurements of the same tissue per subject (e.g., multiple regions of the brain). Results: We first deconvolve the largest bulk RNA-seq dataset of autism (Parikshak et al., 2016; n ¼ 97) and identify hundreds of differentially expressed genes in autism in neurons and astrocytes (FDR < 0.1). In another example, CTS expression of the BrainSpan atlas, which profiles expression patterns of the developing human brain (492 tissue samples from 35 subjects), demonstrates potential insights into processes associated with neurodevelopmental disorders. Our analyses reveal clear CTS co-expression networks that, when combined with genetic findings in autism spectrum disorder (ASD), identify a cluster of co-expressed ASD-associated genes and implicate immature neurons in ASD risk (p-value ¼ 3e-4). Conclusions: The proposed statistical method has the potential to increase the value of bulk transcriptome resources by producing CTS gene expression and co-expression networks, which in turn can yield critical clues regarding the etiology of complex diseases.

Phase II PsychENCODE Acknowledgment Statement

Spectral Learning of Binomial HMMs for DNA Methylation Data

ArXiv, 2018

Author(s): Zhang, Chicheng; Mukamel, Eran A; Chaudhuri, Kamalika | Abstract: We consider learning... more Author(s): Zhang, Chicheng; Mukamel, Eran A; Chaudhuri, Kamalika | Abstract: We consider learning parameters of Binomial Hidden Markov Models, which may be used to model DNA methylation data. The standard algorithm for the problem is EM, which is computationally expensive for sequences of the scale of the mammalian genome. Recently developed spectral algorithms can learn parameters of latent variable models via tensor decomposition, and are highly efficient for large data. However, these methods have only been applied to categorial HMMs, and the main challenge is how to extend them to Binomial HMMs while still retaining computational efficiency. We address this challenge by introducing a new feature-map based approach that exploits specific properties of Binomial HMMs. We provide theoretical performance guarantees for our algorithm and evaluate it on real DNA methylation data.

Sharp : Statistical analysis of super-resolution and hyperacuity from microscopes to retinas

Decision letter: Subcellular sequencing of single neurons reveals the dendritic transcriptome of GABAergic interneurons

eLife, 2020

Although mRNAs are localized in the processes of excitatory neurons, it is still unclear whether ... more Although mRNAs are localized in the processes of excitatory neurons, it is still unclear whether interneurons also localize a large population of mRNAs. In addition, the variability in the localized mRNA population within and between cell types is unknown. Here we describe the unbiased transcriptomic characterization of the subcellular compartments of hundreds of single neurons. We separately profiled the dendritic and somatic transcriptomes of individual rat hippocampal neurons and investigated mRNA abundances in the soma and dendrites of single glutamatergic and GABAergic neurons. We found that, like their excitatory counterparts, interneurons contain a rich repertoire of~4000 mRNAs. We observed more cell type-specific features among somatic transcriptomes than their associated dendritic transcriptomes. Finally, using celltype-specific metabolic labeling of isolated neurites, we demonstrated that the processes of glutamatergic and, notably, GABAergic neurons were capable of local translation, suggesting mRNA localization and local translation are general properties of neurons.

Thermodynamics and the matter of life

Science, 2020

A scientist considers life's genesis through the physics of Exodus What is life? Seventy-five... more A scientist considers life's genesis through the physics of Exodus What is life? Seventy-five years after Erwin Schrödinger took up this fundamental human question, another physicist, Jeremy England, offers a bold update. His new book, Every Life Is on Fire, explores the physics of what makes some configurations of matter lifelike and others inert.

776. Simultaneous Intra- And Extracranial Recording of Prefrontal Neural Activity in Awake, Behaving Rats

Biological Psychiatry, 2017

Background: Depression is characterized by deficits in cognitive control, including impaired perf... more Background: Depression is characterized by deficits in cognitive control, including impaired performance after errors. Particularly, event-related potential (ERP) studies have shown that these impairments are linked to potentiated responses in paralimbic regions, coupled with reduced recruitment of cognitive control regions (dorsolateral prefrontal cortex). Despite these advances, several gaps remain. First, it is unclear whether such disruptions persist after remission. Second, little is known about whether similar post-error deficits emerge in rodent models relevant to depression. Methods: 128-channel ERPs were recorded while 30 unmedicated individuals with remitted depression (rMDD) and 34 healthy controls performed an Eriksen Flanker task before and after an acute psychosocial stressor. In rats, posterror behavioral adjustments were evaluated during a 5-choice serial reaction time task after treatment with corticotropinreleasing factor (CRF), a peptide capable of inducing depression-like phenotypes in rodents. In a second rat cohort, we tested whether abnormal post-error adjustments could be reversed by treatment with JDTic, a kappa-opioid receptor antagonist that produces antidepressant-like effects. Results: In humans, the acute stressor reduced frontocingulate activation for the rMDDbut not controlgroup, in regions critically implicated in cognitive control. Stress-induced blunting in frontocingulate activation was associated with dysregulated endocrinological (cortisol) and affective responses to the stressor. In rats, CRF significantly degraded post-error accuracy, but this effect was reduced by JDTic. Conclusions: ERP markers indicate that cognitive control deficits persist after remission, pointing to a potential mechanism for increased relapse risk. Highlighting translational potential, abnormal post-error behavioral adjustments could be recapitulated in a rodent model (CRF administration) relevant to depression.

Phase diagram for unzipping DNA with long-range interactions

Physical review. E, Statistical, nonlinear, and soft matter physics, 2002

We present a critique and extension of the mean-field approach to the mechanical pulling transiti... more We present a critique and extension of the mean-field approach to the mechanical pulling transition in bound polymer systems. Our model is motivated by the theoretically and experimentally important examples of adsorbed polymers and double-stranded DNA. We focus on the case in which quenched disorder in the sequence of monomers is unimportant for the statistical mechanics, but we include excluded volume interactions between monomers. Our phase diagram for the critical pulling force shows an interesting reentrant phase at low temperatures which should be observable in both disordered and homogenous polymer systems. We also consider the case of nonequilibrium pulling, in which the external force probes the molecule's local, rather than global structure. The dynamics of the pulling transition in such experiments could illuminate the polymer's loop structure, which depends on the nature of excluded volume interactions.

Dissipationless spin current in anisotropic p-doped semiconductors

Physical Review B, 2004

Recently, dissipationless spin current has been predicted for the p-doped semiconductors with spi... more Recently, dissipationless spin current has been predicted for the p-doped semiconductors with spinorbit coupling. Here we investigate the effect of spherical symmetry breaking on the dissipationless spin current, and obtain values of the intrinsic spin Hall conducitivity for realistic semiconductor band structures with cubic symmetry.

Biophysical modeling and optical imaging tools for studies of cerebellar motor learning

Motor learning is a precious capacity that humans, from toddlers to athletes and concert pianists... more Motor learning is a precious capacity that humans, from toddlers to athletes and concert pianists, rely on to move with coordination and grace. The neural circuit in the cerebellum that helps us learn new movements and adjust our performance of familiar reflexes is remarkable for its quasi-crystalline architecture, which has been conserved at the cellular level across vertebrate species. This thesis develops and applies tools based on biophysical and computational modeling of neural circuits, as well as analysis of data sets from optical ...

Topological Spin Current in Anisotropic p-Doped Semiconductors

Abstract We present a derivation of the dissipationless electric-field induced topological spin-c... more Abstract We present a derivation of the dissipationless electric-field induced topological spin-current in realistic, anisotropic semiconductors, which extends the isotropic model system first described by Murakami, Nagaosa and Zhang. We find a smaller value of the spin conductance in the anisotropic material than would be predicted based on a spherical approximation for the band structure, although the decrease is only 5 to 20% in real materials. This extension of the previous isotropic model shows that the spin-current is a ...

The BRAIN Initiative Cell Census Network Data Ecosystem: A User’s Guide

Characterizing cellular diversity at different levels of biological organization across data moda... more Characterizing cellular diversity at different levels of biological organization across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also required to manipulate cell types in controlled ways, and to understand their variation and vulnerability in brain disorders. TheBRAIN Initiative Cell Census Network (BICCN)is an integrated network of data generating centers, data archives and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain and demonstration of prototypes for human and non-human primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed, and to accessing and using the BICCN data and its extensive resources, including theBRAIN Cell Data Center (BCDC)which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecos...

Dnmt3a knockout in excitatory neurons impairs postnatal synapse maturation and increases the repressive histone modification H3K27me3

eLife

Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive co... more Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive complex 2 (PRC2), are known to regulate neuronal development and function. However, their respective contributions to brain maturation are unknown. We found that conditional loss of the de novo DNA methyltransferase Dnmt3a in mouse excitatory neurons altered expression of synapse-related genes, stunted synapse maturation, and impaired working memory and social interest. At the genomic level, loss of Dnmt3a abolished postnatal accumulation of CG and non-CG DNA methylation, leaving adult neurons with an unmethylated, fetal-like epigenomic pattern at ~222,000 genomic regions. The PRC2-associated histone modification, H3K27me3, increased at many of these sites. Our data support a dynamic interaction between two fundamental modes of epigenetic repression during postnatal maturation of excitatory neurons, which together confer robustness on neuronal regulation.

Robust enhancer-gene regulation identified by single-cell transcriptomes and epigenomes

Integrating single-cell transcriptomes and epigenomes across diverse cell types can link genes wi... more Integrating single-cell transcriptomes and epigenomes across diverse cell types can link genes with the cis-regulatory elements (CREs) that control expression. Gene co-expression across cell types confounds simple correlation-based analysis and results in high false prediction rates. We developed a procedure that controls for co-expression between genes and integrates multiple molecular modalities, and used it to identify >10,000 gene-CRE pairs that contribute to gene expression programs in different cell types in the mouse brain.

A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex

Nature, 2021

Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased sam... more Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain1–3. With the proliferation of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of cell-type organization. Here we generated transcriptomes and epigenomes from more than 500,000 individual cells in the mouse primary motor cortex, a structure that has an evolutionarily conserved role in locomotion. We developed computational and statistical methods to integrate multimodal data and quantitatively validate cell-type reproducibility. The resulting reference atlas—containing over 56 neuronal cell types that are highly replicable across analysis methods, sequencing technologies and modalities—is a comprehensive molecular and genomic account of the diverse neuronal and non-neuronal cell types in the mouse primary motor cortex. The atlas includes a population of excitatory neurons that resemble...

A multimodal cell census and atlas of the mammalian primary motor cortex

ABSTRACTWe report the generation of a multimodal cell census and atlas of the mammalian primary m... more ABSTRACTWe report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal an...

TH72. The Role of Dna (Hydroxy) Methylation in Epigenetic Regulation of Excitatory and Inhibitory Neurons in the Prefrontal Cortex of Patients with Schizophrenia

European Neuropsychopharmacology, 2021

Evolution of cellular diversity in primary motor cortex of human, marmoset monkey, and mouse

The primary motor cortex (M1) is essential for voluntary fine motor control and is functionally c... more The primary motor cortex (M1) is essential for voluntary fine motor control and is functionally conserved across mammals. Using high-throughput transcriptomic and epigenomic profiling of over 450,000 single nuclei in human, marmoset monkey, and mouse, we demonstrate a broadly conserved cellular makeup of this region, whose similarity mirrors evolutionary distance and is consistent between the transcriptome and epigenome. The core conserved molecular identity of neuronal and non-neuronal types allowed the generation of a cross-species consensus cell type classification and inference of conserved cell type properties across species. Despite overall conservation, many species specializations were apparent, including differences in cell type proportions, gene expression, DNA methylation, and chromatin state. Few cell type marker genes were conserved across species, providing a short list of candidate genes and regulatory mechanisms responsible for conserved features of homologous cell t...

Comprehensive analysis of single cell ATAC-seq data with SnapATAC

Nature Communications, 2021

Identification of the cis-regulatory elements controlling cell-type specific gene expression patt... more Identification of the cis-regulatory elements controlling cell-type specific gene expression patterns is essential for understanding the origin of cellular diversity. Conventional assays to map regulatory elements via open chromatin analysis of primary tissues is hindered by sample heterogeneity. Single cell analysis of accessible chromatin (scATAC-seq) can overcome this limitation. However, the high-level noise of each single cell profile and the large volume of data pose unique computational challenges. Here, we introduce SnapATAC, a software package for analyzing scATAC-seq datasets. SnapATAC dissects cellular heterogeneity in an unbiased manner and map the trajectories of cellular states. Using the Nyström method, SnapATAC can process data from up to a million cells. Furthermore, SnapATAC incorporates existing tools into a comprehensive package for analyzing single cell ATAC-seq dataset. As demonstration of its utility, SnapATAC is applied to 55,592 single-nucleus ATAC-seq profi...

Epigenomic Diversity of Cortical Projection Neurons in the Mouse Brain

SummaryNeuronal cell types are classically defined by their molecular properties, anatomy, and fu... more SummaryNeuronal cell types are classically defined by their molecular properties, anatomy, and functions. While recent advances in single-cell genomics have led to high-resolution molecular characterization of cell type diversity in the brain, neuronal cell types are often studied out of the context of their anatomical properties. To better understand the relationship between molecular and anatomical features defining cortical neurons, we combined retrograde labeling with single-nucleus DNA methylation sequencing to link epigenomic properties of cell types to neuronal projections. We examined 11,827 single neocortical neurons from 63 cortico-cortical (CC) and cortico-subcortical long-distance projections. Our results revealed unique epigenetic signatures of projection neurons that correspond to their laminar and regional location and projection patterns. Based on their epigenomes, intra-telencephalic (IT) cells projecting to different cortical targets could be further distinguished,...

Using the Power of Single-Nucleus Epigenomics to Map the Molecular Complexity of the Adult Brain

Biological Psychiatry, 2020

type information, although the data can be noisy and typically are derived from a small number of... more type information, although the data can be noisy and typically are derived from a small number of subjects. Methods: Complementing these approaches, we develop a statistical method to estimate subject-level cell-type-specific (CTS) gene expression by borrowing information across multiple measurements of the same tissue per subject (e.g., multiple regions of the brain). Results: We first deconvolve the largest bulk RNA-seq dataset of autism (Parikshak et al., 2016; n ¼ 97) and identify hundreds of differentially expressed genes in autism in neurons and astrocytes (FDR < 0.1). In another example, CTS expression of the BrainSpan atlas, which profiles expression patterns of the developing human brain (492 tissue samples from 35 subjects), demonstrates potential insights into processes associated with neurodevelopmental disorders. Our analyses reveal clear CTS co-expression networks that, when combined with genetic findings in autism spectrum disorder (ASD), identify a cluster of co-expressed ASD-associated genes and implicate immature neurons in ASD risk (p-value ¼ 3e-4). Conclusions: The proposed statistical method has the potential to increase the value of bulk transcriptome resources by producing CTS gene expression and co-expression networks, which in turn can yield critical clues regarding the etiology of complex diseases.