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SATB2 organizes the 3D genome architecture of cognition in cortical neurons [CUT&RUN]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE222608 | GEO | 2024/01/22

REPOSITORIES: GEO

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SATB2 organizes the 3D genome architecture of cognition in cortical neurons

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 | GSE222609 | GEO

SATB2 organizes the 3D genome architecture of cognition in cortical neurons [ATAC-seq]

2024-01-22 | GSE222607 | GEO

SATB2 organizes the 3D genome architecture of cognition in cortical neurons [Hi-C]

2024-01-22 | GSE222606 | GEO

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

2024-01-22 | GSE244285 | 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 Epigenome-Wide Analysis of Socioeconomic Position and Tumor DNA Methylation in Breast Cancer Patients

Project description:Background: Disadvantaged socioeconomic position (SEP), including lower educational attainment and household income, may influence cancer risk and outcomes. We hypothesized that DNA methylation could function as an intermediary epigenetic mechanism that internalizes and reflects the biological impact of SEP. Methods: Based on tumor DNA methylation data from the Illumina 450K array from 694 breast cancer patients in the Women’s Circle of Health Study, we conducted an epigenome-wide analysis in relation to educational attainment and household income. Functional impact of the identified CpG sites was explored in silico using data from publicly available databases. Results: We identified 25 CpG sites associated with household income at an array-wide significance level, but none with educational attainment. Two of the top CpG sites, cg00452016 and cg01667837, were in promoter regions of NNT and GPR37, respectively, with multiple epigenetic regulatory features identified in each region. NNT is involved in -adrenergic stress signaling and inflammatory responses, whereas GPR37 is involved in neurological and immune responses. For both loci, gene expression was inversely correlated to the levels of DNA methylation. The associations were consistent between Black and White women, and did not differ by tumor estrogen receptor (ER) status. Conclusions: In a large breast cancer patient population, we discovered evidence of the significant biological impact of household income on the tumor DNA methylome, including genes in the -adrenergic stress and immune response pathways. Our findings support biological effects of socioeconomic status on tumor tissues which might be relevant to cancer development and progression.

2023-03-31 | GSE226569 | GEO

Loss of neuronal 3D chromatin organization causes transcriptional and behavioral deficits related to serotonergic dysfunction

Project description:The interior of the eukaryotic cell nucleus is a highly organized 3D structure. In mature hippocampal and cortical pyramidal neurons, transcriptionally silent DNA is typically compacted in a few clusters referred to as chromocenters that are strongly stained with DNA intercalating agents like DAPI and whose function is still uncertain. We found that this 3D structure was severely disrupted by the incorporation of the chimeric histone H2BGFP into neuronal chromatin. Experiments in inducible and forebrain restricted bitransgenic mice demonstrated that the expression of this histone alters the higher-order organization of neuronal heterochromatin and causes a complex behavioral phenotype that includes hyperactivity, and social interaction, prepulse inhibition and cognitive defects. This phenotype was associated with highly specific transcriptional deficits that affected several serotonin receptor genes located at the edge of gene desert regions. Pharmacological and electrophysiological experiments indicate that this epigenetically-induced hyposerotonergic state may underlie the behavioral defects. Our results suggest a new role for perinuclear heterochromatin and chromocenter organization in the epigenetic regulation of neuronal gene expression and mental illness. We used microarrays to detect differential gene expression in transgenic mice expressing histone H2BGFP in the forebrain. We obtained triplicate samples (biological replicates) of either genotype (wild-type and H2BGFP mice). Each sample contained pooled total RNA from the hippocampi of 2 three-month old genotype-matched mice.

2014-07-18 | E-GEOD-48437 | biostudies-arrayexpress

LOSS OF NEURONAL TET2 ENHANCES HIPPOCAMPAL-DEPENDENT COGNITIVE FUNCTION

Project description:Chromatin methylation has emerged as a critical modulator of neuronal plasticity and cognitive function. Notwithstanding, the role of enzymes that demethylate DNA remain to be fully explored. Here we report that loss of ten eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), in adult neurons enhances cognitive function. In the adult mouse hippocampus, we detected an enrichment of Tet2 in neurons. Abrogation of neuronal Tet2 in vitro altered synaptic-plasticity related gene expression. We observed that loss of Tet2 in mature glutamatergic neurons in adult mice resulted in differential hydroxymethylation on genes involved in synaptic transmission in the hippocampus. Correspondingly, RNA sequencing identified changes in both long-term potentiation pathways and immune-related genes linked to synaptic plasticity. Functionally, loss of neuronal Tet2 improved performance on hippocampal-dependent spatial and associative memory tasks. Ultimately, this work identifies neuronal Tet2 as a molecular target to enhance cognitive function.

2021-04-13 | GSE171947 | GEO

Loss of neuronal 3D chromatin organization causes transcriptional and behavioral deficits related to serotonergic dysfunction [ChIP-seq]

Project description:The interior of the neuronal cell nucleus is a highly organized 3-dimensional (3D) structure in which regions of the genome that are millions of bases apart participate in specialized sub-structures with dedicated functions. To investigate neuronal chromatin organization and dynamics in vivo, we generated bitransgenic mice that express histone GFP-tagged H2B in principal neurons of the forebrain. Surprisingly, the expression of this chimeric histone in mature neurons causes chromocenter declustering and disrupts the association of heterochromatin with the nuclear lamina. The loss of these structures does not affect neuronal viability but is associated with specific transcriptional and behavioral deficits related to serotonergic dysfunction. Overall, our results demonstrate that the 3D-organization of chromatin in the neuronal nucleus supports an additional level of epigenetic regulation of gene expression that critically influences neuronal function and indicate that some loci associated with neuropsychiatric disorders may be particularly sensitive to changes in chromatin architecture. Genome-wide profiling by high throughput sequencing of H3K27me3 in the adult hippocampus of CaMKII-tTA/tetO-H2BGFP (H2BGFP) and their wild-type littermates mice (WT). Chromatin immunoprecipitation (ChIP) was carried out using pooled hippocampal tissue from 3 mice (one hippocampus per mouse). One DNA library was constructed per genotype. Each DNA library was prepared from pooled immunoprecipitated DNA from 4 independent ChIP assays. In total, tissue from 12 different mice was used to prepare each DNA library. 60% of a lane was used to perform single end (1x50bp) multiplex sequencing in HiSeq 2500 apparatus (Illumina). Each library, was sequenced in duplicate (in two independent sequencing runs. Technical replicates).

2014-07-18 | E-GEOD-56809 | biostudies-arrayexpress

ChIP-seq for Satb2 in E15 cortex

Project description:The goal of the study was to identify the binding site of SATB2 in wild-ype cortex by performing ChIP-seq using SATB2 antibody. E15 cortical tissues were dissected, lysed and fixed. Chromatin was prepared by sonication. Sequences bound by SATB2 protein was precipitated using a SATB2 antibody. Sequencing was performed on Illumina Genome Analyzer II. SATB2 binding peaks were called using MACS. ChIP for Satb2, followed by sequencing on Illumina Genome Analyzer II platform

2015-09-08 | E-GEOD-68910 | biostudies-arrayexpress

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