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1.
Mol Cell ; 84(4): 621-639.e9, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38244545

RESUMO

The DNA-binding protein SATB2 is genetically linked to human intelligence. We studied its influence on the three-dimensional (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 a 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 CCCTC-binding factor (CTCF) to set up the chromatin landscape of pyramidal neurons for cognitive processes.


Assuntos
Proteínas de Ligação à Região de Interação com a Matriz , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neurônios/metabolismo , Fator de Ligação a CCCTC/metabolismo , Cromatina/genética , Cromatina/metabolismo , Genoma , Cognição , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo
2.
Front Mol Biosci ; 10: 1258902, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38028548

RESUMO

Background: Rare endocrine cancers such as Adrenocortical Carcinoma (ACC) present a serious diagnostic and prognostication challenge. The knowledge about ACC pathogenesis is incomplete, and patients have limited therapeutic options. Identification of molecular drivers and effective biomarkers is required for timely diagnosis of the disease and stratify patients to offer the most beneficial treatments. In this study we demonstrate how machine learning methods integrating multi-omics data, in combination with system biology tools, can contribute to the identification of new prognostic biomarkers for ACC. Methods: ACC gene expression and DNA methylation datasets were downloaded from the Xena Browser (GDC TCGA Adrenocortical Carcinoma cohort). A highly correlated multi-omics signature discriminating groups of samples was identified with the data integration analysis for biomarker discovery using latent components (DIABLO) method. Additional regulators of the identified signature were discovered using Clarivate CBDD (Computational Biology for Drug Discovery) network propagation and hidden nodes algorithms on a curated network of molecular interactions (MetaBase™). The discriminative power of the multi-omics signature and their regulators was delineated by training a random forest classifier using 55 samples, by employing a 10-fold cross validation with five iterations. The prognostic value of the identified biomarkers was further assessed on an external ACC dataset obtained from GEO (GSE49280) using the Kaplan-Meier estimator method. An optimal prognostic signature was finally derived using the stepwise Akaike Information Criterion (AIC) that allowed categorization of samples into high and low-risk groups. Results: A multi-omics signature including genes, micro RNA's and methylation sites was generated. Systems biology tools identified additional genes regulating the features included in the multi-omics signature. RNA-seq, miRNA-seq and DNA methylation sets of features revealed a high power to classify patients from stages I-II and stages III-IV, outperforming previously identified prognostic biomarkers. Using an independent dataset, associations of the genes included in the signature with Overall Survival (OS) data demonstrated that patients with differential expression levels of 8 genes and 4 micro RNA's showed a statistically significant decrease in OS. We also found an independent prognostic signature for ACC with potential use in clinical practice, combining 9-gene/micro RNA features, that successfully predicted high-risk ACC cancer patients. Conclusion: Machine learning and integrative analysis of multi-omics data, in combination with Clarivate CBDD systems biology tools, identified a set of biomarkers with high prognostic value for ACC disease. Multi-omics data is a promising resource for the identification of drivers and new prognostic biomarkers in rare diseases that could be used in clinical practice.

3.
bioRxiv ; 2023 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-37503149

RESUMO

Here, we construct genome-scale maps for R-loops, three-stranded nucleic acid structures comprised of a DNA/RNA hybrid and a displaced single strand of DNA, in the proliferative and differentiated zones of the human prenatal brain. We show that R-loops are abundant in the progenitor-rich germinal matrix, with preferential formation at promoters slated for upregulated expression at later stages of differentiation, including numerous neurodevelopmental risk genes. RNase H1-mediated contraction of the genomic R-loop space in neural progenitors shifted differentiation toward the neuronal lineage and was associated with transcriptomic alterations and defective functional and structural neuronal connectivity in vivo and in vitro. Therefore, R-loops are important for fine-tuning differentiation-sensitive gene expression programs of neural progenitor cells.

4.
Nat Commun ; 12(1): 7243, 2021 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-34903713

RESUMO

Regulatory mechanisms associated with repeat-rich sequences and chromosomal conformations in mature neurons remain unexplored. Here, we map cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic B2NeuN+ megabase-scaling subcompartment. Single molecule long-read sequencing and comparative Hi-C chromosomal contact mapping in wild-derived SPRET/EiJ (Mus spretus) and laboratory inbred C57BL/6J (Mus musculus) reveal neuronal reconfigurations tracking recent ERV2 expansions in the murine germline, with significantly higher B2NeuN+ contact frequencies at sites with ongoing insertions in Mus musculus. Neuronal ablation of the retrotransposon silencer Kmt1e/Setdb1 triggers B2NeuN+ disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly with infiltration of dendrites . We conclude that neuronal megabase-scale chromosomal architectures include an evolutionarily adaptive heterochromatic organization which, upon perturbation, results in transcriptional dysregulation and unleashes ERV2 proviruses with strong neuronal tropism.


Assuntos
Cromossomos/metabolismo , Neurônios/metabolismo , Retroelementos/genética , Animais , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Cromossomos/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Retrovirus Endógenos/genética , Evolução Molecular , Amplificação de Genes , Inativação Gênica , Genes de Partícula A Intracisternal/genética , Genoma Viral/genética , Gliose/genética , Gliose/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Camundongos , Microglia/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/virologia , Provírus/genética , Vírion/genética , Vírion/metabolismo
5.
Front Mol Neurosci ; 14: 664912, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025350

RESUMO

In early development, the environment triggers mnemonic epigenomic programs resulting in memory and learning experiences to confer cognitive phenotypes into adulthood. To uncover how environmental stimulation impacts the epigenome and genome organization, we used the paradigm of environmental enrichment (EE) in young mice constantly receiving novel stimulation. We profiled epigenome and chromatin architecture in whole cortex and sorted neurons by deep-sequencing techniques. Specifically, we studied chromatin accessibility, gene and protein regulation, and 3D genome conformation, combined with predicted enhancer and chromatin interactions. We identified increased chromatin accessibility, transcription factor binding including CTCF-mediated insulation, differential occupancy of H3K36me3 and H3K79me2, and changes in transcriptional programs required for neuronal development. EE stimuli led to local genome re-organization by inducing increased contacts between chromosomes 7 and 17 (inter-chromosomal). Our findings support the notion that EE-induced learning and memory processes are directly associated with the epigenome and genome organization.

6.
Genome Med ; 12(1): 19, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075678

RESUMO

BACKGROUND: Midbrain dopaminergic neurons (MDN) represent 0.0005% of the brain's neuronal population and mediate cognition, food intake, and metabolism. MDN are also posited to underlay the neurobiological dysfunction of schizophrenia (SCZ), a severe neuropsychiatric disorder that is characterized by psychosis as well as multifactorial medical co-morbidities, including metabolic disease, contributing to markedly increased morbidity and mortality. Paradoxically, however, the genetic risk sequences of psychosis and traits associated with metabolic disease, such as body mass, show very limited overlap. METHODS: We investigated the genomic interaction of SCZ with medical conditions and traits, including body mass index (BMI), by exploring the MDN's "spatial genome," including chromosomal contact landscapes as a critical layer of cell type-specific epigenomic regulation. Low-input Hi-C protocols were applied to 5-10 × 103 dopaminergic and other cell-specific nuclei collected by fluorescence-activated nuclei sorting from the adult human midbrain. RESULTS: The Hi-C-reconstructed MDN spatial genome revealed 11 "Euclidean hot spots" of clustered chromatin domains harboring risk sequences for SCZ and elevated BMI. Inter- and intra-chromosomal contacts interconnecting SCZ and BMI risk sequences showed massive enrichment for brain-specific expression quantitative trait loci (eQTL), with gene ontologies, regulatory motifs and proteomic interactions related to adipogenesis and lipid regulation, dopaminergic neurogenesis and neuronal connectivity, and reward- and addiction-related pathways. CONCLUSIONS: We uncovered shared nuclear topographies of cognitive and metabolic risk variants. More broadly, our PsychENCODE sponsored Hi-C study offers a novel genomic approach for the study of psychiatric and medical co-morbidities constrained by limited overlap of their respective genetic risk architectures on the linear genome.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Polimorfismo Genético , Locos de Características Quantitativas , Esquizofrenia/genética , Adipogenia , Animais , Índice de Massa Corporal , Cromossomos/genética , Cognição , Humanos , Metabolismo dos Lipídeos , Mesencéfalo/citologia , Mesencéfalo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese , Esquizofrenia/metabolismo , Esquizofrenia/patologia
7.
Nat Commun ; 10(1): 4112, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511512

RESUMO

Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus. C11orf46 haploinsufficiency was associated with hypoplasia of the corpus callosum. C11orf46 knockdown disrupted transcallosal projections and was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with intellectual disability. Multiple genes encoding key regulators of axonal development, including Sema6a, were hyperexpressed in C11orf46-knockdown neurons. RNA-guided epigenetic editing of Sema6a gene promoters via a dCas9-SunTag system with C11orf46 binding normalized SEMA6A expression and rescued transcallosal dysconnectivity via repressive chromatin remodeling by the SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain's connectome via gene-targeted designer activators and repressor proteins.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Corpo Caloso/metabolismo , Epigênese Genética , Edição de Genes , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , Semaforinas/genética , Animais , Axônios/metabolismo , Epigenoma , Regulação da Expressão Gênica , Predisposição Genética para Doença , Células HEK293 , Histona-Lisina N-Metiltransferase , Humanos , Camundongos Endogâmicos C57BL , Rede Nervosa/metabolismo , Neuritos/metabolismo , Fenótipo , Ligação Proteica , Proteínas Metiltransferases/metabolismo
8.
Curr Opin Neurobiol ; 59: 112-119, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31255842

RESUMO

The 'non-linear' genome, or the spatial proximity of non-contiguous sequences, emerges as an important regulatory layer for genome organization and function, including transcriptional regulation. Here, we review recent genome-scale chromosome conformation mappings ('Hi-C') in developing and adult human and mouse brain. Neural differentiation is associated with widespread remodeling of the chromosomal contact map, reflecting dynamic changes in cell-type-specific gene expression programs, with a massive (estimated 20-50%) net loss of chromosomal contacts that is specific for the neuronal lineage. Hi-C datasets provided an unexpected link between locus-specific abnormal expansion of repeat sequences positioned at the boundaries of self-associating topological chromatin domains, and monogenic neurodevelopmental and neurodegenerative disease. Furthermore, integrative cell-type-specific Hi-C and transcriptomic analysis uncovered an expanded genomic risk space for sequences conferring liability for schizophrenia and other cognitive disease. We predict that spatial genome exploration will deliver radically new insights into the brain nucleome in health and disease.


Assuntos
Doenças Neurodegenerativas , Animais , Cromatina , Cognição , Genoma , Genômica , Humanos
9.
Science ; 362(6420)2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30545851

RESUMO

To explore the developmental reorganization of the three-dimensional genome of the brain in the context of neuropsychiatric disease, we monitored chromosomal conformations in differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread developmental remodeling of the chromosomal contact map and included interactions anchored in common variant sequences that confer heritable risk for schizophrenia. We describe cell type-specific chromosomal connectomes composed of schizophrenia risk variants and their distal targets, which altogether show enrichment for genes that regulate neuronal connectivity and chromatin remodeling, and evidence for coordinated transcriptional regulation and proteomic interaction of the participating genes. Developmentally regulated chromosomal conformation changes at schizophrenia-relevant sequences disproportionally occurred in neurons, highlighting the existence of cell type-specific disease risk vulnerabilities in spatial genome organization.


Assuntos
Cromossomos Humanos/química , Conectoma , Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento , Predisposição Genética para Doença , Células-Tronco Neurais/citologia , Neurogênese/genética , Esquizofrenia/genética , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Células Cultivadas , Cromatina/química , Montagem e Desmontagem da Cromatina , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Células-Tronco Neurais/metabolismo , Neuroglia/citologia , Neurônios/citologia , Neurônios/metabolismo , Conformação de Ácido Nucleico , Mapas de Interação de Proteínas/genética , Proteômica , Risco , Transcrição Gênica , Transcriptoma
10.
Dev Neurobiol ; 76(9): 956-71, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26600420

RESUMO

A prevalent developmental mechanism for the assignment of cell identities is the production of spatiotemporal concentration gradients of extracellular signaling molecules that are interpreted by the responding cells. One of such signaling systems is the Shh gradient that controls neuronal subtype identity in the ventral spinal cord. Using loss and gain of function approaches in chick and mouse embryos, we show here that the fibroblast growth factor (FGF) signaling pathway is required to restrict the domains of ventral gene expression as neuroepithelial cells become exposed to Shh during caudal extension of the embryo. FGF signaling activates the expression of the Shh receptor and negative pathway regulator Patched 2 (Ptch2) and therefore can enhance a negative feedback loop that restrains the activity of the pathway. Thus, we identify one of the mechanisms by which FGF signaling acts as a modulator of the onset of Shh signaling activity in the context of coordination of ventral patterning and caudal axis extension. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 956-971, 2016.


Assuntos
Fatores de Crescimento de Fibroblastos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas Hedgehog/fisiologia , Transdução de Sinais/fisiologia , Corno Ventral da Medula Espinal/fisiologia , Animais , Embrião de Galinha , Humanos , Camundongos , Corno Ventral da Medula Espinal/embriologia
11.
Neuron ; 76(6): 1108-22, 2012 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-23259947

RESUMO

In migrating neurons, the centrosome nucleates and anchors a polarized network of microtubules that directs organelle movements. We report here that the mother centriole of neurons migrating tangentially from the medial ganglionic eminence (MGE) assembles a short primary cilium and exposes this cilium to the cell surface by docking to the plasma membrane in the leading process. Primary cilia are built by intraflagellar transport (IFT), which is also required for Sonic hedgehog (Shh) signal transduction in vertebrates. We show that Shh pathway perturbations influenced the leading process morphology and dynamics of MGE cells. Whereas Shh favored the exit of MGE cells away from their tangential migratory paths in the developing cortex, cyclopamine or invalidation of IFT genes maintained MGE cells in the tangential paths. Our findings show that signals transmitted through the primary cilium promote the escape of future GABAergic interneurons from their tangential routes to colonize the cortical plate.


Assuntos
Movimento Celular/fisiologia , Centrossomo/fisiologia , Córtex Cerebral/embriologia , Cílios/fisiologia , Proteínas Hedgehog/fisiologia , Neurônios/fisiologia , Animais , Gânglios da Base/citologia , Gânglios da Base/embriologia , Polaridade Celular/fisiologia , Centríolos/fisiologia , Córtex Cerebral/citologia , Camundongos , Camundongos Mutantes Neurológicos , Camundongos Transgênicos , Neurogênese/fisiologia , Neurônios/citologia , Transdução de Sinais/fisiologia
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