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  1. Article: Cell type-specific enrichment of somatic aneuploidy in the mammalian brain.

    Mukamel, Eran A / Liu, Hanqing / Behrens, M Margarita / Ecker, Joseph R

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Somatic mutations alter the genomes of a subset of an individual's brain ... ...

    Abstract Somatic mutations alter the genomes of a subset of an individual's brain cells
    Language English
    Publishing date 2023-12-19
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.18.572285
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Joint profiling of histone modifications and transcriptome in single cells from mouse brain.

    Zhu, Chenxu / Zhang, Yanxiao / Li, Yang Eric / Lucero, Jacinta / Behrens, M Margarita / Ren, Bing

    Nature methods

    2021  Volume 18, Issue 3, Page(s) 283–292

    Abstract: Genome-wide profiling of histone modifications can reveal not only the location and activity state of regulatory elements, but also the regulatory mechanisms involved in cell-type-specific gene expression during development and disease pathology. ... ...

    Abstract Genome-wide profiling of histone modifications can reveal not only the location and activity state of regulatory elements, but also the regulatory mechanisms involved in cell-type-specific gene expression during development and disease pathology. Conventional assays to profile histone modifications in bulk tissues lack single-cell resolution. Here we describe an ultra-high-throughput method, Paired-Tag, for joint profiling of histone modifications and transcriptome in single cells to produce cell-type-resolved maps of chromatin state and transcriptome in complex tissues. We used this method to profile five histone modifications jointly with transcriptome in the adult mouse frontal cortex and hippocampus. Integrative analysis of the resulting maps identified distinct groups of genes subject to divergent epigenetic regulatory mechanisms. Our single-cell multiomics approach enables comprehensive analysis of chromatin state and gene regulation in complex tissues and characterization of gene regulatory programs in the constituent cell types.
    MeSH term(s) Animals ; Cell Line, Tumor ; Chromatin/metabolism ; Epigenesis, Genetic/genetics ; Frontal Lobe/cytology ; Frontal Lobe/metabolism ; Gene Expression Profiling ; Gene Expression Regulation/genetics ; HeLa Cells ; Hippocampus/cytology ; Hippocampus/metabolism ; Histone Code/genetics ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Protein Processing, Post-Translational ; Regulatory Sequences, Nucleic Acid/genetics ; Single-Cell Analysis ; Transcriptome/genetics
    Chemical Substances Chromatin
    Language English
    Publishing date 2021-02-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2169522-2
    ISSN 1548-7105 ; 1548-7091
    ISSN (online) 1548-7105
    ISSN 1548-7091
    DOI 10.1038/s41592-021-01060-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Author Correction: Conserved and divergent gene regulatory programs of the mammalian neocortex.

    Zemke, Nathan R / Armand, Ethan J / Wang, Wenliang / Lee, Seoyeon / Zhou, Jingtian / Li, Yang Eric / Liu, Hanqing / Tian, Wei / Nery, Joseph R / Castanon, Rosa G / Bartlett, Anna / Osteen, Julia K / Li, Daofeng / Zhuo, Xiaoyu / Xu, Vincent / Chang, Lei / Dong, Keyi / Indralingam, Hannah S / Rink, Jonathan A /
    Xie, Yang / Miller, Michael / Krienen, Fenna M / Zhang, Qiangge / Taskin, Naz / Ting, Jonathan / Feng, Guoping / McCarroll, Steven A / Callaway, Edward M / Wang, Ting / Lein, Ed S / Behrens, M Margarita / Ecker, Joseph R / Ren, Bing

    Nature

    2024  Volume 625, Issue 7996, Page(s) E26

    Language English
    Publishing date 2024-01-09
    Publishing country England
    Document type Published Erratum
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-023-07013-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Abnormal Gamma Oscillations in N-Methyl-D-Aspartate Receptor Hypofunction Models of Schizophrenia.

    Jadi, Monika P / Behrens, M Margarita / Sejnowski, Terrence J

    Biological psychiatry

    2015  Volume 79, Issue 9, Page(s) 716–726

    Abstract: N-methyl-D-aspartate receptor (NMDAR) hypofunction in parvalbumin-expressing (PV+) inhibitory neurons (INs) may contribute to symptoms in patients with schizophrenia (SZ). This hypothesis was inspired by studies in humans involving NMDAR antagonists that ...

    Abstract N-methyl-D-aspartate receptor (NMDAR) hypofunction in parvalbumin-expressing (PV+) inhibitory neurons (INs) may contribute to symptoms in patients with schizophrenia (SZ). This hypothesis was inspired by studies in humans involving NMDAR antagonists that trigger SZ symptoms. Animal models of SZ using neuropharmacology and genetic knockouts have successfully replicated some of the key observations in human subjects involving alteration of gamma band oscillations (GBO) observed in electroencephalography and magnetoencephalography signals. However, it remains to be seen if NMDAR hypofunction in PV+ neurons is fundamental to the phenotype observed in these models. In this review, we discuss some of the key computational models of GBO and their predictions in the context of NMDAR hypofunction in INs. While PV+ INs have been the main focus of SZ studies in animal models, we also discuss the implications of NMDAR hypofunction in other types of INs using computational models for GBO modulation in the visual cortex.
    MeSH term(s) Action Potentials ; Animals ; Cerebral Cortex/physiopathology ; Electroencephalography ; GABAergic Neurons/metabolism ; GABAergic Neurons/physiology ; Gamma Rhythm ; Humans ; Interneurons/metabolism ; Interneurons/physiology ; Models, Neurological ; Parvalbumins/metabolism ; Receptors, N-Methyl-D-Aspartate/genetics ; Receptors, N-Methyl-D-Aspartate/physiology ; Schizophrenia/physiopathology ; gamma-Aminobutyric Acid/physiology
    Chemical Substances Parvalbumins ; Receptors, N-Methyl-D-Aspartate ; gamma-Aminobutyric Acid (56-12-2)
    Language English
    Publishing date 2015-07-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 209434-4
    ISSN 1873-2402 ; 0006-3223
    ISSN (online) 1873-2402
    ISSN 0006-3223
    DOI 10.1016/j.biopsych.2015.07.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Ketamine independently modulated power and phase-coupling of theta oscillations in Sp4 hypomorphic mice.

    Wang, Xin / Pinto-Duarte, António / Behrens, M Margarita / Zhou, Xianjin / Sejnowski, Terrence J

    PloS one

    2018  Volume 13, Issue 3, Page(s) e0193446

    Abstract: Reduced expression of Sp4, the murine homolog of human SP4, a risk gene of multiple psychiatric disorders, led to N-methyl-D-aspartate (NMDA) hypofunction in mice, producing behavioral phenotypes reminiscent of schizophrenia, including hypersensitivity ... ...

    Abstract Reduced expression of Sp4, the murine homolog of human SP4, a risk gene of multiple psychiatric disorders, led to N-methyl-D-aspartate (NMDA) hypofunction in mice, producing behavioral phenotypes reminiscent of schizophrenia, including hypersensitivity to ketamine. As accumulating evidence on molecular mechanisms and behavioral phenotypes established Sp4 hypomorphism as a promising animal model, systems-level neural circuit mechanisms of Sp4 hypomorphism, especially network dynamics underlying cognitive functions, remain poorly understood. We attempted to close this gap in knowledge in the present study by recording multi-channel epidural electroencephalogram (EEG) from awake behaving wildtype and Sp4 hypomorphic mice. We characterized cortical theta-band power and phase-coupling phenotypes, a known neural circuit substrate underlying cognitive functions, and further studied the effects of a subanesthetic dosage of ketamine on theta abnormalities unique to Sp4 hypomorphism. Sp4 hypomorphic mice had markedly elevated theta power localized frontally and parietally, a more pronounced theta phase progression along the neuraxis, and a stronger frontal-parietal theta coupling. Acute subanesthetic ketamine did not affect theta power in wildtype animals but significantly reduced it in Sp4 hypomorphic mice, nearly completely neutralizing their excessive frontal/parietal theta power. Ketamine did not significantly alter cortical theta phase progression in either wildtype or Sp4 hypomorphic animals, but significantly strengthened cortical theta phase-coupling in wildtype, but not in Sp4 hypomorphic animals. Our results suggested that the resting-state phenotypes of cortical theta oscillations unique to Sp4 hypomorphic mice closely mimicked a schizophrenic endophenotype. Further, ketamine independently modulated Sp4 hypomorphic anomalies in theta power and phase-coupling, suggesting separate underlying neural circuit mechanisms.
    MeSH term(s) Animals ; Brain/drug effects ; Brain/physiology ; Electroencephalography/methods ; Excitatory Amino Acid Antagonists/pharmacology ; Female ; Ketamine/pharmacology ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Phenotype ; Sp4 Transcription Factor/deficiency ; Sp4 Transcription Factor/genetics ; Theta Rhythm/drug effects ; Theta Rhythm/physiology
    Chemical Substances Excitatory Amino Acid Antagonists ; Sp4 Transcription Factor ; Sp4 protein, mouse ; Ketamine (690G0D6V8H)
    Language English
    Publishing date 2018-03-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0193446
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Robust enhancer-gene regulation identified by single-cell transcriptomes and epigenomes.

    Xie, Fangming / Armand, Ethan J / Yao, Zizhen / Liu, Hanqing / Bartlett, Anna / Behrens, M Margarita / Li, Yang Eric / Lucero, Jacinta D / Luo, Chongyuan / Nery, Joseph R / Pinto-Duarte, Antonio / Poirion, Olivier B / Preissl, Sebastian / Rivkin, Angeline C / Tasic, Bosiljka / Zeng, Hongkui / Ren, Bing / Ecker, Joseph R / Mukamel, Eran A

    Cell genomics

    2023  Volume 3, Issue 7, Page(s) 100342

    Abstract: Single-cell sequencing could help to solve the fundamental challenge of linking millions of cell-type-specific enhancers with their target genes. However, this task is confounded by patterns of gene co-expression in much the same way that genetic ... ...

    Abstract Single-cell sequencing could help to solve the fundamental challenge of linking millions of cell-type-specific enhancers with their target genes. However, this task is confounded by patterns of gene co-expression in much the same way that genetic correlation due to linkage disequilibrium confounds fine-mapping in genome-wide association studies (GWAS). We developed a non-parametric permutation-based procedure to establish stringent statistical criteria to control the risk of false-positive associations in enhancer-gene association studies (EGAS). We applied our procedure to large-scale transcriptome and epigenome data from multiple tissues and species, including the mouse and human brain, to predict enhancer-gene associations genome wide. We tested the functional validity of our predictions by comparing them with chromatin conformation data and causal enhancer perturbation experiments. Our study shows how controlling for gene co-expression enables robust enhancer-gene linkage using single-cell sequencing data.
    Language English
    Publishing date 2023-06-19
    Publishing country United States
    Document type Journal Article
    ISSN 2666-979X
    ISSN (online) 2666-979X
    DOI 10.1016/j.xgen.2023.100342
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Ketamine independently modulated power and phase-coupling of theta oscillations in Sp4 hypomorphic mice.

    Xin Wang / António Pinto-Duarte / M Margarita Behrens / Xianjin Zhou / Terrence J Sejnowski

    PLoS ONE, Vol 13, Iss 3, p e

    2018  Volume 0193446

    Abstract: Reduced expression of Sp4, the murine homolog of human SP4, a risk gene of multiple psychiatric disorders, led to N-methyl-D-aspartate (NMDA) hypofunction in mice, producing behavioral phenotypes reminiscent of schizophrenia, including hypersensitivity ... ...

    Abstract Reduced expression of Sp4, the murine homolog of human SP4, a risk gene of multiple psychiatric disorders, led to N-methyl-D-aspartate (NMDA) hypofunction in mice, producing behavioral phenotypes reminiscent of schizophrenia, including hypersensitivity to ketamine. As accumulating evidence on molecular mechanisms and behavioral phenotypes established Sp4 hypomorphism as a promising animal model, systems-level neural circuit mechanisms of Sp4 hypomorphism, especially network dynamics underlying cognitive functions, remain poorly understood. We attempted to close this gap in knowledge in the present study by recording multi-channel epidural electroencephalogram (EEG) from awake behaving wildtype and Sp4 hypomorphic mice. We characterized cortical theta-band power and phase-coupling phenotypes, a known neural circuit substrate underlying cognitive functions, and further studied the effects of a subanesthetic dosage of ketamine on theta abnormalities unique to Sp4 hypomorphism. Sp4 hypomorphic mice had markedly elevated theta power localized frontally and parietally, a more pronounced theta phase progression along the neuraxis, and a stronger frontal-parietal theta coupling. Acute subanesthetic ketamine did not affect theta power in wildtype animals but significantly reduced it in Sp4 hypomorphic mice, nearly completely neutralizing their excessive frontal/parietal theta power. Ketamine did not significantly alter cortical theta phase progression in either wildtype or Sp4 hypomorphic animals, but significantly strengthened cortical theta phase-coupling in wildtype, but not in Sp4 hypomorphic animals. Our results suggested that the resting-state phenotypes of cortical theta oscillations unique to Sp4 hypomorphic mice closely mimicked a schizophrenic endophenotype. Further, ketamine independently modulated Sp4 hypomorphic anomalies in theta power and phase-coupling, suggesting separate underlying neural circuit mechanisms.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article: Comparative single cell epigenomic analysis of gene regulatory programs in the rodent and primate neocortex.

    Zemke, Nathan R / Armand, Ethan J / Wang, Wenliang / Lee, Seoyeon / Zhou, Jingtian / Li, Yang Eric / Liu, Hanqing / Tian, Wei / Nery, Joseph R / Castanon, Rosa G / Bartlett, Anna / Osteen, Julia K / Li, Daofeng / Zhuo, Xiaoyu / Xu, Vincent / Miller, Michael / Krienen, Fenna M / Zhang, Qiangge / Taskin, Naz /
    Ting, Jonathan / Feng, Guoping / McCarroll, Steven A / Callaway, Edward M / Wang, Ting / Behrens, M Margarita / Lein, Ed S / Ecker, Joseph R / Ren, Bing

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Sequence divergence ... ...

    Abstract Sequence divergence of
    Language English
    Publishing date 2023-04-08
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.08.536119
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Iterative single-cell multi-omic integration using online learning.

    Gao, Chao / Liu, Jialin / Kriebel, April R / Preissl, Sebastian / Luo, Chongyuan / Castanon, Rosa / Sandoval, Justin / Rivkin, Angeline / Nery, Joseph R / Behrens, Margarita M / Ecker, Joseph R / Ren, Bing / Welch, Joshua D

    Nature biotechnology

    2021  Volume 39, Issue 8, Page(s) 1000–1007

    Abstract: Integrating large single-cell gene expression, chromatin accessibility and DNA methylation datasets requires general and scalable computational approaches. Here we describe online integrative non-negative matrix factorization (iNMF), an algorithm for ... ...

    Abstract Integrating large single-cell gene expression, chromatin accessibility and DNA methylation datasets requires general and scalable computational approaches. Here we describe online integrative non-negative matrix factorization (iNMF), an algorithm for integrating large, diverse and continually arriving single-cell datasets. Our approach scales to arbitrarily large numbers of cells using fixed memory, iteratively incorporates new datasets as they are generated and allows many users to simultaneously analyze a single copy of a large dataset by streaming it over the internet. Iterative data addition can also be used to map new data to a reference dataset. Comparisons with previous methods indicate that the improvements in efficiency do not sacrifice dataset alignment and cluster preservation performance. We demonstrate the effectiveness of online iNMF by integrating more than 1 million cells on a standard laptop, integrating large single-cell RNA sequencing and spatial transcriptomic datasets, and iteratively constructing a single-cell multi-omic atlas of the mouse motor cortex.
    MeSH term(s) Algorithms ; Animals ; Computational Biology/methods ; Machine Learning ; Mice ; Multivariate Analysis ; Single-Cell Analysis/methods ; Transcriptome/genetics
    Language English
    Publishing date 2021-04-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/s41587-021-00867-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Conserved and divergent gene regulatory programs of the mammalian neocortex.

    Zemke, Nathan R / Armand, Ethan J / Wang, Wenliang / Lee, Seoyeon / Zhou, Jingtian / Li, Yang Eric / Liu, Hanqing / Tian, Wei / Nery, Joseph R / Castanon, Rosa G / Bartlett, Anna / Osteen, Julia K / Li, Daofeng / Zhuo, Xiaoyu / Xu, Vincent / Chang, Lei / Dong, Keyi / Indralingam, Hannah S / Rink, Jonathan A /
    Xie, Yang / Miller, Michael / Krienen, Fenna M / Zhang, Qiangge / Taskin, Naz / Ting, Jonathan / Feng, Guoping / McCarroll, Steven A / Callaway, Edward M / Wang, Ting / Lein, Ed S / Behrens, M Margarita / Ecker, Joseph R / Ren, Bing

    Nature

    2023  Volume 624, Issue 7991, Page(s) 390–402

    Abstract: Divergence of cis-regulatory elements drives species-specific ... ...

    Abstract Divergence of cis-regulatory elements drives species-specific traits
    MeSH term(s) Animals ; Humans ; Mice ; Callithrix/genetics ; Chromatin/genetics ; Chromatin/metabolism ; Conserved Sequence/genetics ; DNA Methylation ; DNA Transposable Elements/genetics ; Epigenome ; Evolution, Molecular ; Gene Expression Regulation/genetics ; Gene Regulatory Networks ; Macaca/genetics ; Mammals/genetics ; Motor Cortex/cytology ; Motor Cortex/metabolism ; Multiomics ; Neocortex/cytology ; Neocortex/metabolism ; Regulatory Sequences, Nucleic Acid/genetics ; Single-Cell Analysis ; Transcription Factors/metabolism ; Genetic Variation/genetics
    Chemical Substances Chromatin ; DNA Transposable Elements ; Transcription Factors
    Language English
    Publishing date 2023-12-13
    Publishing country England
    Document type Comparative Study ; Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-023-06819-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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