X chromosome agents of sexual differentiation

Nature Reviews Endocrinology, Journal Year: 2022, Volume and Issue: 18(9), P. 574 - 583

Published: June 15, 2022

Language: Английский

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Redefining cerebral palsies as a diverse group of neurodevelopmental disorders with genetic aetiology

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(9), P. 542 - 555

Published: Aug. 3, 2023

Language: Английский

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Escape from X inactivation is directly modulated by levels of Xist non-coding RNA

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 24, 2024

ABSTRACT In placental females, one copy of the two X chromosomes is largely silenced during a narrow developmental time window, in process mediated by non-coding RNA Xist 1 . Here, we demonstrate that can initiate X-chromosome inactivation (XCI) well beyond early embryogenesis. By modifying its endogenous level, show has capacity to actively silence genes escape XCI both neuronal progenitor cells (NPCs) and vivo , mouse embryos. We also plays direct role eliminating TAD-like structures associated with clusters escapee on inactive chromosome, this dependent Xist’s initiation partner, SPEN 2 further function suppressing gene expression escapees topological domain formation reversible for up seven days post-induction, but sustained up-regulation leads progressively irreversible silencing CpG island DNA methylation facultative escapees. Thus, distinctive transcriptional regulatory topologies chromosome actively, directly - reversibly controlled throughout life.

Language: Английский

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Phenotypes and Genotypes in Patients with SMC1A-Related Developmental and Epileptic Encephalopathy

Genes, Journal Year: 2023, Volume and Issue: 14(4), P. 852 - 852

Published: March 31, 2023

The X-linked SMC1A gene encodes a core subunit of the cohesin complex that plays pivotal role in genome organization and regulation. Pathogenic variants are often dominant-negative cause Cornelia de Lange syndrome (CdLS) with growth retardation typical facial features; however, rare developmental epileptic encephalopathy (DEE) intractable early-onset epilepsy is absent CdLS. Unlike male-to-female ratio 1:2 those CdLS associated variants, SMC1A-DEE loss-of-function (LOF) found exclusively females due to presumed lethality males. It unclear how different or DEE. Here, we report on phenotypes genotypes three DEE novo including novel splice-site variant. We also summarize 41 known characterize common patient-specific features. Interestingly, compared 33 LOFs detected throughout gene, 7/8 non-LOFs specifically located N/C-terminal ATPase head central hinge domain, both which predicted affect assembly, thus mimicking LOFs. Along characterization X-chromosome inactivation (XCI) transcription, these strongly suggest differential dosage effect closely manifestation phenotypes.

Language: Английский

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Sex chromosomes and gonads modify microglial-mediated pathology in a mouse model of Alzheimer’s disease

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: March 13, 2025

Alzheimer's disease (AD) is a neurodegenerative disorder disproportionally affecting women with sex-specific manifestations and therapeutic responses. Microglial-mediated inflammation occurs in response to perpetuates processes, fundamental sex differences microglia may contribute these biases. Both chromosomes gonad-derived hormones shape immune responses, but their contribution immune-mediated mechanisms underlying the bias AD unclear. Crossing Four Core Genotype (FCG) model separate chromosome hormone effects 5xFAD model, we found complement impacted microgliosis, neuroinflammation, plaque burden neuritic dystrophy. Modification of pathology largely correlated influenced remodeling microglial CD11c expression. Our results provide potential trajectories for studying targeting microglial-mediated emphasize complex interplay between during AD.

Language: Английский

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Stochasticity in genetics and gene regulation

Philosophical Transactions of the Royal Society B Biological Sciences, Journal Year: 2024, Volume and Issue: 379(1900)

Published: March 4, 2024

Development from fertilized egg to functioning multi-cellular organism requires precision. There is no precision, and often survival, without plasticity. Plasticity conferred partly by stochastic variation, present inherently in all biological systems. Gene expression levels fluctuate ubiquitously through transcription, alternative splicing, translation turnover. Small differences gene are exploited trigger early differentiation, conferring distinct function on selected individual cells setting motion regulatory interactions. Non-selected then acquire new functions along the spatio-temporal developmental trajectory. The differentiation process has many components. Meiotic segregation, mitochondrial partitioning, X-inactivation dynamic DNA binding of transcription factor assemblies—all exhibit randomness. Non-random generally signals deleterious X-linked mutations. Correct neural wiring, such as retina brain, arises repeated confirmatory activity connections made randomly. In immune system development, both B-cell antibody generation emergence balanced T-cell categories begin trial error followed functional selection. Aberrant selection processes lead dysfunction. sequence variants also arise events: some involving environmental fluctuation (radiation or presence pollutants), genetic repair malfunction. phenotypic outcome mutations fluid. Mutations may be advantageous circumstances, others. This article part a discussion meeting issue ‘Causes consequences development disease’.

Language: Английский

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Population variability in X-chromosome inactivation across 10 mammalian species

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 18, 2024

One of the two X-chromosomes in female mammals is epigenetically silenced embryonic stem cells by X-chromosome inactivation. This creates a mosaic expressing either maternal or paternal X allele. The inactivation ratio, proportion inactivated parental alleles, varies widely among individuals, representing largest instance epigenetic variability within mammalian populations. While various contributing factors to are recognized, namely stochastic and/or genetic effects, their relative contributions poorly understood. due part limited cross-species analysis, making it difficult distinguish between generalizable species-specific mechanisms for ratio variability. To address this gap, we measure ratios ten species (9531 individual samples), ranging from rodents primates, and compare strength models explaining Our results demonstrate stochasticity general explanatory model population mammals, while play minor role.

Language: Английский

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Precision Exercise Medicine: Sex Specific Differences in Immune and CNS Responses to Physical Activity

Brain Plasticity, Journal Year: 2022, Volume and Issue: 8(1), P. 65 - 77

Published: May 31, 2022

Physical activity is a powerful lifestyle factor capable of improving cognitive function, modifying the risk for dementia associated with neurodegeneration and possibly slowing neurodegenerative disease progression in both men women. However, women show differences biological responses to physical vulnerabilities onset, outcome diseases, prompting question whether sex-specific regulatory mechanisms might differentially modulate benefits exercise on brain. Mechanistic studies aimed better understand how improves brain health function suggest that responds by overall reducing neuroinflammation increasing neuroplasticity. Here, we review emerging literature considering immune system response as potential mechanism which affects Although addressing sex this light limited, initial findings influence exercise, lay out scientific foundation support very much needed investigating effects sex-differences neurobiology. Considering neurobiological hallmarks will help enhance our understanding also improve development treatments interventions diseases central nervous system.

Language: Английский

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Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(24), P. 17377 - 17377

Published: Dec. 12, 2023

Research into Alzheimer's Disease (AD) describes a link between AD and the resident immune cells of brain, microglia. Further, this suspected is thought to have underlying sex effects, although mechanisms these effects are only just beginning be understood. Many insights result policies put in place by funding agencies such as National Institutes Health (NIH) consider biological variable (SABV) move towards precision medicine due continued lackluster therapeutic options. The purpose review provide an updated assessment current research that summarizes differences pertaining microglia their varied responses AD.

Language: Английский

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Sex-linked genetic mechanisms and atrial fibrillation risk

European Journal of Medical Genetics, Journal Year: 2022, Volume and Issue: 65(4), P. 104459 - 104459

Published: Feb. 19, 2022

Atrial fibrillation (AF) is a cardiac condition characterised by an irregular heartbeat, atrial pathology and elevated downstream risk of thrombosis heart failure, as well neurological sequelae including stroke dementia. The prevalence presentation of, factors for, therapeutic responses to, AF differ sex, this sex bias may be partially explained in terms genetics. Here, we consider four sex-linked genetic mechanisms that influence sex-biased phenotypes related to provide examples each: X-linked gene dosage, genomic imprinting, autosomal expression, male-limited Y-linked expression. We highlight novel candidate genes pathways warrant further investigation clinical preclinical studies. Understanding the biological basis differences should allow better prediction disease risk, identification risk/protective factors, development more effective sex-tailored interventions.

Language: Английский

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