Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits

The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function could yield insights into disease pathogenes...

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Published inNature communications Vol. 12; no. 1; p. 6749
Main Authors Pahl, Matthew C., Doege, Claudia A., Hodge, Kenyaita M., Littleton, Sheridan H., Leonard, Michelle E., Lu, Sumei, Rausch, Rick, Pippin, James A., De Rosa, Maria Caterina, Basak, Alisha, Bradfield, Jonathan P., Hammond, Reza K., Boehm, Keith, Berkowitz, Robert I., Lasconi, Chiara, Su, Chun, Chesi, Alessandra, Johnson, Matthew E., Wells, Andrew D., Voight, Benjamin F., Leibel, Rudolph L., Cousminer, Diana L., Grant, Struan F. A.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 19.11.2021
Nature Publishing Group
Nature Portfolio
Subjects
13/100
14/63
45/22
45/23
45/91
631/208/177
631/208/200
Body weight
Cell Differentiation - genetics
Cell Line
Chromatin
Chromosome Mapping
Differentiation
Endocrine system
Gene Expression Regulation, Developmental
Gene mapping
Gene regulation
Gene Regulatory Networks
Genes
Genome-Wide Association Study
High resolution
Homeostasis
Human Embryonic Stem Cells - physiology
Humanities and Social Sciences
Humans
Hypothalamus
Hypothalamus - cytology
Hypothalamus - embryology
multidisciplinary
Multifactorial Inheritance
Neurons - physiology
Pathogenesis
Regulatory Elements, Transcriptional - genetics
Regulatory sequences
RNA-Seq
Science
Science (multidisciplinary)
Stem cells
Online AccessGet full text

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Abstract The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function could yield insights into disease pathogenesis. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generate a high-resolution chromatin architecture atlas of an established embryonic stem cell derived hypothalamic-like neuron model across three stages of in vitro differentiation. We profile accessible chromatin and identify physical contacts between gene promoters and putative cis-regulatory elements to characterize global regulatory landscape changes during hypothalamic differentiation. Next, we integrate these data with GWAS loci for various complex traits, identifying multiple candidate effector genes. Our results reveal common target genes for these traits, potentially affecting core developmental pathways. Our atlas will enable future efforts to determine hypothalamic mechanisms influencing disease susceptibility. Understanding the genetic regulation of hypothalamic function could yield insights into disease pathogenesis, but its inaccessibility has made this challenging. Here the authors present a high-resolution chromatin atlas of a hypothalamic-like neuron model across three stages of differentiation.
AbstractList The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function could yield insights into disease pathogenesis. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generate a high-resolution chromatin architecture atlas of an established embryonic stem cell derived hypothalamic-like neuron model across three stages of in vitro differentiation. We profile accessible chromatin and identify physical contacts between gene promoters and putative cis-regulatory elements to characterize global regulatory landscape changes during hypothalamic differentiation. Next, we integrate these data with GWAS loci for various complex traits, identifying multiple candidate effector genes. Our results reveal common target genes for these traits, potentially affecting core developmental pathways. Our atlas will enable future efforts to determine hypothalamic mechanisms influencing disease susceptibility. Understanding the genetic regulation of hypothalamic function could yield insights into disease pathogenesis, but its inaccessibility has made this challenging. Here the authors present a high-resolution chromatin atlas of a hypothalamic-like neuron model across three stages of differentiation.
The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function could yield insights into disease pathogenesis. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generate a high-resolution chromatin architecture atlas of an established embryonic stem cell derived hypothalamic-like neuron model across three stages of in vitro differentiation. We profile accessible chromatin and identify physical contacts between gene promoters and putative cis-regulatory elements to characterize global regulatory landscape changes during hypothalamic differentiation. Next, we integrate these data with GWAS loci for various complex traits, identifying multiple candidate effector genes. Our results reveal common target genes for these traits, potentially affecting core developmental pathways. Our atlas will enable future efforts to determine hypothalamic mechanisms influencing disease susceptibility.
The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function could yield insights into disease pathogenesis. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generate a high-resolution chromatin architecture atlas of an established embryonic stem cell derived hypothalamic-like neuron model across three stages of in vitro differentiation. We profile accessible chromatin and identify physical contacts between gene promoters and putative cis-regulatory elements to characterize global regulatory landscape changes during hypothalamic differentiation. Next, we integrate these data with GWAS loci for various complex traits, identifying multiple candidate effector genes. Our results reveal common target genes for these traits, potentially affecting core developmental pathways. Our atlas will enable future efforts to determine hypothalamic mechanisms influencing disease susceptibility.Understanding the genetic regulation of hypothalamic function could yield insights into disease pathogenesis, but its inaccessibility has made this challenging. Here the authors present a high-resolution chromatin atlas of a hypothalamic-like neuron model across three stages of differentiation.
Understanding the genetic regulation of hypothalamic function could yield insights into disease pathogenesis, but its inaccessibility has made this challenging. Here the authors present a high-resolution chromatin atlas of a hypothalamic-like neuron model across three stages of differentiation.
Abstract The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function could yield insights into disease pathogenesis. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generate a high-resolution chromatin architecture atlas of an established embryonic stem cell derived hypothalamic-like neuron model across three stages of in vitro differentiation. We profile accessible chromatin and identify physical contacts between gene promoters and putative cis-regulatory elements to characterize global regulatory landscape changes during hypothalamic differentiation. Next, we integrate these data with GWAS loci for various complex traits, identifying multiple candidate effector genes. Our results reveal common target genes for these traits, potentially affecting core developmental pathways. Our atlas will enable future efforts to determine hypothalamic mechanisms influencing disease susceptibility.
ArticleNumber 6749
Author Wells, Andrew D.
Voight, Benjamin F.
Littleton, Sheridan H.
Lu, Sumei
Chesi, Alessandra
Lasconi, Chiara
Su, Chun
Boehm, Keith
Grant, Struan F. A.
Basak, Alisha
Hammond, Reza K.
Johnson, Matthew E.
Doege, Claudia A.
Hodge, Kenyaita M.
Berkowitz, Robert I.
Leonard, Michelle E.
Pippin, James A.
Cousminer, Diana L.
Leibel, Rudolph L.
De Rosa, Maria Caterina
Bradfield, Jonathan P.
Pahl, Matthew C.
Rausch, Rick
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/34799566$$D View this record in MEDLINE/PubMed
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Copyright The Author(s) 2021
2021. The Author(s).
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SSID ssj0000391844
Score 2.472308
Snippet The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight and...
Abstract The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body...
Understanding the genetic regulation of hypothalamic function could yield insights into disease pathogenesis, but its inaccessibility has made this...
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pubmedcentral
proquest
crossref
pubmed
springer
SourceType Open Website
Open Access Repository
Aggregation Database
Index Database
Publisher
StartPage 6749
SubjectTerms 13/100
14/63
45/22
45/23
45/91
631/208/177
631/208/200
Body weight
Cell Differentiation - genetics
Cell Line
Chromatin
Chromosome Mapping
Differentiation
Endocrine system
Gene Expression Regulation, Developmental
Gene mapping
Gene regulation
Gene Regulatory Networks
Genes
Genome-Wide Association Study
High resolution
Homeostasis
Human Embryonic Stem Cells - physiology
Humanities and Social Sciences
Humans
Hypothalamus
Hypothalamus - cytology
Hypothalamus - embryology
multidisciplinary
Multifactorial Inheritance
Neurons - physiology
Pathogenesis
Regulatory Elements, Transcriptional - genetics
Regulatory sequences
RNA-Seq
Science
Science (multidisciplinary)
Stem cells
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Title Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits
URI https://link.springer.com/article/10.1038/s41467-021-27001-4
https://www.ncbi.nlm.nih.gov/pubmed/34799566
https://www.proquest.com/docview/2599273205
https://search.proquest.com/docview/2600284002
https://pubmed.ncbi.nlm.nih.gov/PMC8604959
https://doaj.org/article/87b561b18c73423d8f4af95c3968229a
Volume 12
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