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Article ; Online: AAV Deployment of Enhancer-Based Expression Constructs In Vivo in Mouse Brain.

Warren, Tracy L / Lambert, Jason T / Nord, Alex S

Journal of visualized experiments : JoVE

2022 , Issue 181

Abstract: Enhancers are binding platforms for a diverse array of transcription factors that drive specific expression patterns of tissue- and cell-type-specific genes. Multiple means of assessing non-coding DNA and various chromatin states have proven useful in ... ...

Abstract	Enhancers are binding platforms for a diverse array of transcription factors that drive specific expression patterns of tissue- and cell-type-specific genes. Multiple means of assessing non-coding DNA and various chromatin states have proven useful in predicting the presence of enhancer sequences in the genome, but validating the activity of these sequences and finding the organs and developmental stages they are active in is a labor-intensive process. Recent advances in adeno-associated virus (AAV) vectors have enabled the widespread delivery of transgenes to mouse tissues, enabling in vivo enhancer testing without necessitating a transgenic animal. This protocol shows how a reporter construct that expresses EGFP under the control of a minimal promoter, which does not drive significant expression on its own, can be used to study the activity patterns of candidate enhancer sequences in the mouse brain. An AAV-packaged reporter construct is delivered to the mouse brain and incubated for 1-4 weeks, after which the animal is sacrificed, and brain sections are observed under a microscope. EGFP appears in cells in which the tested enhancer is sufficient to initiate gene expression, pinpointing the location and developmental stage in which the enhancer is active in the brain. Standard cloning methods, low-cost AAV packaging, and expanding AAV serotypes and methods for in vivo delivery and standard imaging readout make this an accessible approach for the study of how gene expression is regulated in the brain.
MeSH term(s)	Animals ; Brain/metabolism ; Dependovirus/genetics ; Dependovirus/metabolism ; Genetic Vectors/genetics ; Mice ; Promoter Regions, Genetic ; Transgenes
Language	English
Publishing date	2022-03-31
Publishing country	United States
Document type	Journal Article ; Video-Audio Media ; Research Support, N.I.H., Extramural
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/62650
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Learning about mammalian gene regulation from functional enhancer assays in the mouse.

Nord, Alex S

Genomics

2015 Volume 106, Issue 3, Page(s) 178–184

Abstract: Enhancer biology is emerging as a critical area of research that informs studies of evolution, development, and disease. From early experiments that defined and mapped the first enhancers to recent enhancer models of human disease, functional experiments ...

Abstract	Enhancer biology is emerging as a critical area of research that informs studies of evolution, development, and disease. From early experiments that defined and mapped the first enhancers to recent enhancer models of human disease, functional experiments in the mouse have played a central role in revealing enhancer biology. Three decades of in vivo enhancer studies in mouse have laid the groundwork for the current understanding of mammalian enhancers, demonstrating the developmental and tissue-specific activity of enhancers and illuminating general features of enhancer evolution and function. Recent studies offer an emerging perspective on the importance of chromosomal context, combinatorial enhancer activity, and the functional consequences of enhancer sequence variation. This review describes the basic principles of functional testing in mouse, summarizes the contributions these studies have made to our understanding of enhancer biology, and describes limitations and future outlook of in vivo mouse enhancer studies.
MeSH term(s)	Animals ; Enhancer Elements, Genetic ; Evolution, Molecular ; Gene Expression Regulation, Developmental ; Genetic Variation/genetics ; Humans ; Mammals/genetics ; Mice ; Transcription Factors/genetics
Chemical Substances	Transcription Factors
Language	English
Publishing date	2015-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	356334-0
ISSN	1089-8646 ; 0888-7543
ISSN (online)	1089-8646
ISSN	0888-7543
DOI	10.1016/j.ygeno.2015.06.008
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Article ; Online: Neurobiological functions of transcriptional enhancers.

Nord, Alex S / West, Anne E

Nature neuroscience

2019 Volume 23, Issue 1, Page(s) 5–14

Abstract: Transcriptional enhancers are regulatory DNA elements that underlie the specificity and dynamic patterns of gene expression. Over the past decade, large-scale functional genomics projects have driven transformative progress in our understanding of ... ...

Abstract	Transcriptional enhancers are regulatory DNA elements that underlie the specificity and dynamic patterns of gene expression. Over the past decade, large-scale functional genomics projects have driven transformative progress in our understanding of enhancers. These data have relevance for identifying mechanisms of gene regulation in the CNS, elucidating the function of non-coding regulatory sequences in neurobiology and linking sequence variation within enhancers to genetic risk for neurological and psychiatric disorders. However, the sheer volume and complexity of genomic data presents a challenge to interpreting enhancer function in normal and pathogenic neurobiological processes. Here, to advance the application of genome-scale enhancer data, we offer a primer on current models of enhancer function in the CNS, we review how enhancers regulate gene expression across the neuronal lifespan, and we suggest how emerging findings regarding the role of non-coding sequence variation offer opportunities for understanding brain disorders and developing new technologies for neuroscience.
MeSH term(s)	Animals ; Brain/physiology ; Enhancer Elements, Genetic/physiology ; Gene Expression Regulation/physiology ; Humans ; Neurons/physiology ; Transcription, Genetic/physiology
Language	English
Publishing date	2019-11-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1420596-8
ISSN	1546-1726 ; 1097-6256
ISSN (online)	1546-1726
ISSN	1097-6256
DOI	10.1038/s41593-019-0538-5
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Zs.A 4891: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Association of neurotransmitter pathway polygenic risk with specific symptom profiles in psychosis.

Warren, Tracy L / Tubbs, Justin D / Lesh, Tyler A / Corona, Mylena B / Pakzad, Sarvenaz S / Albuquerque, Marina D / Singh, Praveena / Zarubin, Vanessa / Morse, Sarah J / Sham, Pak Chung / Carter, Cameron S / Nord, Alex S

Molecular psychiatry

2024

Abstract: A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients ... ...

Abstract	A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 205 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.
Language	English
Publishing date	2024-03-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-024-02457-0
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Zs.A 4812: Show issues

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Article: Learning about mammalian gene regulation from functional enhancer assays in the mouse

Nord, Alex S

Genomics. 2015 Sept., v. 106

2015

Abstract	Enhancer biology is emerging as a critical area of research that informs studies of evolution, development, and disease. From early experiments that defined and mapped the first enhancers to recent enhancer models of human disease, functional experiments in the mouse have played a central role in revealing enhancer biology. Three decades of in vivo enhancer studies in mouse have laid the groundwork for the current understanding of mammalian enhancers, demonstrating the developmental and tissue-specific activity of enhancers and illuminating general features of enhancer evolution and function. Recent studies offer an emerging perspective on the importance of chromosomal context, combinatorial enhancer activity, and the functional consequences of enhancer sequence variation. This review describes the basic principles of functional testing in mouse, summarizes the contributions these studies have made to our understanding of enhancer biology, and describes limitations and future outlook of in vivo mouse enhancer studies.
Keywords	enhancer elements ; evolution ; gene expression regulation ; genes ; human diseases ; mice ; models ; sequence diversity
Language	English
Dates of publication	2015-09
Size	p. 178-184.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	356334-0
ISSN	1089-8646 ; 0888-7543
ISSN (online)	1089-8646
ISSN	0888-7543
DOI	10.1016/j.ygeno.2015.06.008
Database	NAL-Catalogue (AGRICOLA)

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Article: Common CHD8 Genomic Targets Contrast With Model-Specific Transcriptional Impacts of

Wade, A Ayanna / Lim, Kenneth / Catta-Preta, Rinaldo / Nord, Alex S

Frontiers in molecular neuroscience

2019 Volume 11, Page(s) 481

Abstract: The packaging of DNA into chromatin determines the transcriptional potential of cells and is central to eukaryotic gene regulation. Case sequencing studies have revealed mutations to proteins that regulate chromatin state, known as chromatin remodeling ... ...

Abstract	The packaging of DNA into chromatin determines the transcriptional potential of cells and is central to eukaryotic gene regulation. Case sequencing studies have revealed mutations to proteins that regulate chromatin state, known as chromatin remodeling factors, with causal roles in neurodevelopmental disorders. Chromodomain helicase DNA binding protein 8 (
Language	English
Publishing date	2019-01-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2018.00481
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Article: Association of neurotransmitter pathway polygenic risk with specific symptom profiles in psychosis.

Warren, Tracy L / Tubbs, Justin D / Lesh, Tyler A / Corona, Mylena B / Pakzad, Sarvenaz / Albuquerque, Marina / Singh, Praveena / Zarubin, Vanessa / Morse, Sarah / Sham, Pak Chung / Carter, Cameron S / Nord, Alex S

medRxiv : the preprint server for health sciences

2023

Abstract	A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 206 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.
Language	English
Publishing date	2023-11-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.24.23290465
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Article ; Online: In vivo

Wade, A Ayanna / van den Ameele, Jelle / Cheetham, Seth W / Yakob, Rebecca / Brand, Andrea H / Nord, Alex S

iScience

2021 Volume 24, Issue 11, Page(s) 103234

Abstract: Genetic studies of autism have revealed causal roles for chromatin remodeling gene mutations. Chromodomain helicase DNA binding protein 8 ( ...

Abstract	Genetic studies of autism have revealed causal roles for chromatin remodeling gene mutations. Chromodomain helicase DNA binding protein 8 (
Language	English
Publishing date	2021-10-07
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2021.103234
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Article ; Online: Transcriptional Pathology Evolves over Time in Rat Hippocampus after Lateral Fluid Percussion Traumatic Brain Injury.

Catta-Preta, Rinaldo / Zdilar, Iva / Jenner, Bradley / Doisy, Emily T / Tercovich, Kayleen / Nord, Alex S / Gurkoff, Gene G

Neurotrauma reports

2021 Volume 2, Issue 1, Page(s) 512–525

Abstract: Traumatic brain injury (TBI) causes acute and lasting impacts on the brain, driving pathology along anatomical, cellular, and behavioral dimensions. Rodent models offer an opportunity to study the temporal progression of disease from injury to recovery. ... ...

Abstract	Traumatic brain injury (TBI) causes acute and lasting impacts on the brain, driving pathology along anatomical, cellular, and behavioral dimensions. Rodent models offer an opportunity to study the temporal progression of disease from injury to recovery. Transcriptomic and epigenomic analysis were applied to evaluate gene expression in ipsilateral hippocampus at 1 and 14 days after sham (
Language	English
Publishing date	2021-11-23
Publishing country	United States
Document type	Journal Article
ISSN	2689-288X
ISSN (online)	2689-288X
DOI	10.1089/neur.2021.0021
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Article: Combinatorial transcription factor binding encodes cis-regulatory wiring of forebrain GABAergic neurogenesis.

Catta-Preta, Rinaldo / Lindtner, Susan / Ypsilanti, Athena / Price, James / Abnousi, Armen / Su-Feher, Linda / Wang, Yurong / Juric, Ivan / Jones, Ian R / Akiyama, Jennifer A / Hu, Ming / Shen, Yin / Visel, Axel / Pennacchio, Len A / Dickel, Diane / Rubenstein, John L R / Nord, Alex S

bioRxiv : the preprint server for biology

2023

Abstract: Transcription factors (TFs) bind combinatorially to genomic cis-regulatory elements (cREs), orchestrating transcription programs. While studies of chromatin state and chromosomal interactions have revealed dynamic neurodevelopmental cRE landscapes, ... ...

Abstract	Transcription factors (TFs) bind combinatorially to genomic cis-regulatory elements (cREs), orchestrating transcription programs. While studies of chromatin state and chromosomal interactions have revealed dynamic neurodevelopmental cRE landscapes, parallel understanding of the underlying TF binding lags. To elucidate the combinatorial TF-cRE interactions driving mouse basal ganglia development, we integrated ChIP-seq for twelve TFs, H3K4me3-associated enhancer-promoter interactions, chromatin and transcriptional state, and transgenic enhancer assays. We identified TF-cREs modules with distinct chromatin features and enhancer activity that have complementary roles driving GABAergic neurogenesis and suppressing other developmental fates. While the majority of distal cREs were bound by one or two TFs, a small proportion were extensively bound, and these enhancers also exhibited exceptional evolutionary conservation, motif density, and complex chromosomal interactions. Our results provide new insights into how modules of combinatorial TF-cRE interactions activate and repress developmental expression programs and demonstrate the value of TF binding data in modeling gene regulatory wiring.
Language	English
Publishing date	2023-06-28
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.28.546894
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