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Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex

ABSTRACT: There is increasing recognition about the importance of epigenetic dysregulation in neurodevelopmental disorders including autism spectrum disorder and schizophrenia, although the cell-type specific changes in gene regulation across critical periods of brain development have not been fully elucidated. In this study we profiled DNA methylation of purified populations of neuronal (SATB2+) and non-neuronal (SATB2-) cell-types in 47 human fetal and child donors (8 post-conceptual weeks to 8 years old).

ORGANISM(S): Homo sapiens

PROVIDER: GSE289184 | GEO | 2025/03/03

REPOSITORIES: GEO

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DNA methylation dynamics in the prenatal and postnatal human cortex

Project description:There is increasing recognition about the importance of epigenetic dysregulation in neurodevelopmental disorders including autism spectrum disorder and schizophrenia, yet little is known about patterns of gene regulation in the later stages of fetal development and the first decade of life. In this study we profiled changes in DNA methylation, an epigenetic modification to cytosine involved in mediating the developmental regulation of gene expression and function, across human brain development in cortex tissue from 107 human fetal and child donors spanning 6 post-conceptual weeks to 8 years old.

2025-03-03 | GSE289191 | GEO

SATB2-LEMD2 interaction links nuclear shape plasticity to regulation of cognition-related genes

Project description:SATB2, encoding a nuclear chromosomal scaffolding protein, is a schizophrenia risk gene and genetically associated with human intelligence. How SATB2 affects cognition at molecular level is currently unknown. Our data suggest that interactions between SATB2 and the inner nuclear membrane protein LEMD2 orchestrate gene expression programs in pyramidal neurons that are linked to cognitive ability and psychiatric disorder etiology. We show that LEMD2, a candidate component of the A-heterochromatin tether, binds to SATB2 and the two proteins exert overlapping cellular functions. SATB2 is essential for neuronal activity-triggered nuclear envelope plasticity, which requires LEMD2 as well as the ESCRT-III/VPS4 complex. LEMD2-depletion in cortical neurons, like SATB2 ablation, affects the expression of multiple neuronal activity-regulated genes. The gene-sets regulated by LEMD2 and SATB2 significantly overlap and the LEMD2 gene-set is enriched for SATB2-bound genes. In human genetic data, LEMD2-regulated genes are enriched for loss-of-function mutations reported in autism, intellectual disability and schizophrenia and are, like SATB2-regulated genes, associated with cognitive function.

2020-11-29 | GSE157375 | GEO

An activity-mediated transition in transcription in early postnatal neurons [10X]

Project description:The maturation of the mammalian brain occurs after birth, and this stage of neuronal development is frequently impaired in neurological disorders, such as autism and schizophrenia. However, the mechanisms that regulate postnatal brain maturation are poorly defined. By purifying neuronal subpopulations across brain development in mice, we identify a postnatal switch in the transcriptional regulatory circuits that operates in the maturing mammalian brain. We show that this developmental transition includes the formation of hundreds of cell-type-specific neuronal enhancers in the postnatal period that might in part be modulated by neuronal activity. Once selected, these enhancers are active throughout adulthood, suggesting that their formation in early life shapes neuronal identity and regulates mature brain function.

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An activity-mediated transition in transcription in early postnatal neurons [HiChIP]

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An activity-mediated transition in transcription in early postnatal neurons [ATAC-seq]

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SATB2 organizes the 3D genome architecture of cognition in cortical neurons [RNA-Seq]

Project description:The DNA-binding protein SATB2 is genetically linked to human intelligence. We studied its influence on 3D epigenome by mapping chromatin interactions and accessibility in control versus SATB2-deficient cortical neurons. We find that SATB2 affects the chromatin looping between enhancers and promoters of neuronal activity-regulated genes, thus influencing their expression. It also alters A/B compartments, Topologically Associating Domains and Frequently Interacting Regions. Genes linked to SATB2-dependent 3D genome changes are implicated in highly specialized neuronal functions and contribute to cognitive ability and risk for neuropsychiatric and neurodevelopmental disorders. Non-coding DNA regions with SATB2-dependent structure are enriched for common variants associated with educational attainment, intelligence and schizophrenia. Our data establish SATB2 as a cell-type specific 3D genome modulator, which operates both independently and in cooperation with CTCF to set up the chromatin landscape of pyramidal neurons for cognitive processes.

2024-01-22 | GSE244285 | GEO

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