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1.
Annu Rev Cell Dev Biol ; 37: 199-232, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34228506

RESUMO

Nuclei are central hubs for information processing in eukaryotic cells. The need to fit large genomes into small nuclei imposes severe restrictions on genome organization and the mechanisms that drive genome-wide regulatory processes. How a disordered polymer such as chromatin, which has vast heterogeneity in its DNA and histone modification profiles, folds into discernibly consistent patterns is a fundamental question in biology. Outstanding questions include how genomes are spatially and temporally organized to regulate cellular processes with high precision and whether genome organization is causally linked to transcription regulation. The advent of next-generation sequencing, super-resolution imaging, multiplexed fluorescent in situ hybridization, and single-molecule imaging in individual living cells has caused a resurgence in efforts to understand the spatiotemporal organization of the genome. In this review, we discuss structural and mechanistic properties of genome organization at different length scales and examine changes in higher-order chromatin organization during important developmental transitions.


Assuntos
Cromatina , Cromossomos , Cromatina/genética , DNA , Genoma , Hibridização in Situ Fluorescente
2.
Cell ; 171(1): 85-102.e23, 2017 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-28867287

RESUMO

Chromatin modification and higher-order chromosome structure play key roles in gene regulation, but their functional interplay in controlling gene expression is elusive. We have discovered the machinery and mechanism underlying the dynamic enrichment of histone modification H4K20me1 on hermaphrodite X chromosomes during C. elegans dosage compensation and demonstrated H4K20me1's pivotal role in regulating higher-order chromosome structure and X-chromosome-wide gene expression. The structure and the activity of the dosage compensation complex (DCC) subunit DPY-21 define a Jumonji demethylase subfamily that converts H4K20me2 to H4K20me1 in worms and mammals. Selective inactivation of demethylase activity eliminates H4K20me1 enrichment in somatic cells, elevates X-linked gene expression, reduces X chromosome compaction, and disrupts X chromosome conformation by diminishing the formation of topologically associating domains (TADs). Unexpectedly, DPY-21 also associates with autosomes of germ cells in a DCC-independent manner to enrich H4K20me1 and trigger chromosome compaction. Our findings demonstrate the direct link between chromatin modification and higher-order chromosome structure in long-range regulation of gene expression.


Assuntos
Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Regulação da Expressão Gênica , Cromossomo X/química , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Transporte/genética , Mecanismo Genético de Compensação de Dose , Embrião não Mamífero/metabolismo , Histona Desmetilases com o Domínio Jumonji/química , Histona Desmetilases com o Domínio Jumonji/metabolismo , Modelos Moleculares , Mutação , Piperidinas/metabolismo , Alinhamento de Sequência , Tiofenos/metabolismo
3.
Cell ; 165(5): 1197-1208, 2016 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-27133166

RESUMO

Organisms respond to mitochondrial stress through the upregulation of an array of protective genes, often perpetuating an early response to metabolic dysfunction across a lifetime. We find that mitochondrial stress causes widespread changes in chromatin structure through histone H3K9 di-methylation marks traditionally associated with gene silencing. Mitochondrial stress response activation requires the di-methylation of histone H3K9 through the activity of the histone methyltransferase met-2 and the nuclear co-factor lin-65. While globally the chromatin becomes silenced by these marks, remaining portions of the chromatin open up, at which point the binding of canonical stress responsive factors such as DVE-1 occurs. Thus, a metabolic stress response is established and propagated into adulthood of animals through specific epigenetic modifications that allow for selective gene expression and lifespan extension.


Assuntos
Caenorhabditis elegans/fisiologia , Montagem e Desmontagem da Cromatina , Resposta a Proteínas não Dobradas , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/metabolismo , Epigênese Genética , Regulação da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Longevidade , Mitocôndrias/metabolismo
4.
Proc Natl Acad Sci U S A ; 119(37): e2211642119, 2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36067293

RESUMO

Organisms that count X-chromosome number to determine sex utilize dosage compensation mechanisms to balance X-gene expression between sexes. Typically, a regulatory complex is recruited to X chromosomes of one sex to modulate gene expression. A major challenge is to determine the mechanisms that target regulatory complexes specifically to X. Here, we identify critical X-sequence motifs in Caenorhabditis elegans that act synergistically in hermaphrodites to direct X-specific recruitment of the dosage compensation complex (DCC), a condensin complex. We find two DNA motifs that collaborate with a previously defined 12-bp motif called MEX (motif enriched on X) to mediate binding: MEX II, a 26-bp X-enriched motif and Motif C, a 9-bp motif that lacks X enrichment. Inserting both MEX and MEX II into a new location on X creates a DCC binding site equivalent to an endogenous recruitment site, but inserting only MEX or MEX II alone does not. Moreover, mutating MEX, MEX II, or Motif C in endogenous recruitment sites with multiple different motifs dramatically reduces DCC binding in vivo to nearly the same extent as mutating all motifs. Changing the orientation or spacing of motifs also reduces DCC binding. Hence, synergy in DCC binding via combinatorial clustering of motifs triggers DCC assembly specifically on X chromosomes. Using an in vitro DNA binding assay, we refine the features of motifs and flanking sequences that are critical for DCC binding. Our work reveals general principles by which regulatory complexes can be recruited across an entire chromosome to control its gene expression.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Mecanismo Genético de Compensação de Dose , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Análise por Conglomerados , Motivos de Nucleotídeos , Cromossomo X/genética , Cromossomo X/metabolismo
5.
Genome Res ; 31(7): 1187-1202, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34168009

RESUMO

DNA topology and alternative DNA structures are implicated in regulating diverse biological processes. Although biomechanical properties of these structures have been studied extensively in vitro, characterization in vivo, particularly in multicellular organisms, is limited. We devised new methods to map DNA supercoiling and single-stranded DNA in Caenorhabditis elegans embryos and diapause larvae. To map supercoiling, we quantified the incorporation of biotinylated psoralen into DNA using high-throughput sequencing. To map single-stranded DNA, we combined permanganate treatment with genome-wide sequencing of induced double-stranded breaks. We found high levels of negative supercoiling at transcription start sites (TSSs) in embryos. GC-rich regions flanked by a sharp GC-to-AT transition delineate boundaries of supercoil propagation. In contrast to TSSs in embryos, TSSs in diapause larvae showed dramatic reductions in negative supercoiling without concomitant attenuation of transcription, suggesting developmental-stage-specific regulation. To assess whether alternative DNA structures control chromosome architecture and gene expression, we examined DNA supercoiling in the context of X-Chromosome dosage compensation. We showed that the condensin dosage compensation complex creates negative supercoils locally at its highest-occupancy binding sites but found no evidence for large-scale supercoiling domains along X Chromosomes. In contrast to transcription-coupled negative supercoiling, single-strandedness, which is most pronounced at transcript end sites, is dependent on high AT content and symmetrically positioned nucleosomes. We propose that sharp transitions in sequence composition at functional genomic elements constitute a common regulatory code and that DNA structure and propagation of torsional stress at regulatory elements are critical parameters in shaping important developmental events.

6.
Cell ; 139(1): 73-86, 2009 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-19781752

RESUMO

Meiotic crossover (CO) recombination facilitates evolution and accurate chromosome segregation. CO distribution is tightly regulated: homolog pairs receive at least one CO, CO spacing is nonrandom, and COs occur preferentially in short genomic intervals called hotspots. We show that CO number and distribution are controlled on a chromosome-wide basis at the level of DNA double-strand break (DSB) formation by a condensin complex composed of subunits from two known condensins: the C. elegans dosage compensation complex and mitotic condensin II. Disruption of any subunit of the CO-controlling condensin dominantly changes DSB distribution, and thereby COs, and extends meiotic chromosome axes. These phenotypes are cosuppressed by disruption of a chromosome axis element. Our data implicate higher-order chromosome structure in the regulation of CO recombination, provide a model for the rapid evolution of CO hotspots, and show that reshuffling of interchangeable molecular parts can create independent machines with similar architectures but distinct biological functions.


Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Troca Genética , Proteínas de Ligação a DNA/metabolismo , Meiose , Complexos Multiproteicos/metabolismo , Adenosina Trifosfatases/genética , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas Cromossômicas não Histona , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/genética , Humanos , Complexos Multiproteicos/genética , Mutação , Rad51 Recombinase/metabolismo
7.
Mar Drugs ; 21(7)2023 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-37504910

RESUMO

We examined the effect of a dietary seaweed extract-sulfated xylorhamnoglucuronan (SXRG84)-on individuals with inflammatory skin conditions. A subgroup analysis of a larger trial was undertaken, where 44 participants with skin conditions were enrolled in a double-blind placebo-controlled crossover design. Subjects ingested either SXRG84 extract (2 g/day) for six weeks and placebo for six weeks, or vice versa. At baseline, six- and twelve-weeks inflammatory markers and the gut microbiota were assessed, as well as skin assessments using the dermatology quality of life index (DQLI), psoriasis area severity index (PASI) and visual analogue scales (VAS). There were significant differences at weeks six and twelve for pro-inflammatory cytokines IFN-γ (p = 0.041), IL-1ß (p = 0.030), TNF-α (p = 0.008) and the anti-inflammatory cytokine IL-10 (p = 0.026), determined by ANCOVA. These cytokines were all significantly higher at six weeks post placebo compared to twelve weeks post placebo followed by SXRG84 treatment. A total of 23% of participants reported skin improvements, as measured by VAS (mean difference 3.1, p = 0.0005) and the DQLI score (mean difference -2.0, p = 0.049), compared to the 'non-responders'. Thus, the ingestion of SXRG84 for 6 weeks reduced inflammatory cytokines, and a subset of participants saw improvements.


Assuntos
Psoríase , Qualidade de Vida , Humanos , Psoríase/tratamento farmacológico , Citocinas , Fator de Necrose Tumoral alfa , Suplementos Nutricionais , Método Duplo-Cego , Resultado do Tratamento
8.
Proc Natl Acad Sci U S A ; 117(21): 11459-11470, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32385148

RESUMO

Genomic regions preferentially associate with regions of similar transcriptional activity, partitioning genomes into active and inactive compartments within the nucleus. Here we explore mechanisms controlling genome compartment organization in Caenorhabditis elegans and investigate roles for compartments in regulating gene expression. Distal arms of C. elegans chromosomes, which are enriched for heterochromatic histone modifications H3K9me1/me2/me3, interact with each other both in cis and in trans, while interacting less frequently with central regions, leading to genome compartmentalization. Arms are anchored to the nuclear periphery via the nuclear envelope protein CEC-4, which binds to H3K9me. By performing genome-wide chromosome conformation capture experiments (Hi-C), we showed that eliminating H3K9me1/me2/me3 through mutations in the methyltransferase genes met-2 and set-25 significantly impaired formation of inactive Arm and active Center compartments. cec-4 mutations also impaired compartmentalization, but to a lesser extent. We found that H3K9me promotes compartmentalization through two distinct mechanisms: Perinuclear anchoring of chromosome arms via CEC-4 to promote their cis association, and an anchoring-independent mechanism that compacts individual chromosome arms. In both met-2 set-25 and cec-4 mutants, no dramatic changes in gene expression were found for genes that switched compartments or for genes that remained in their original compartment, suggesting that compartment strength does not dictate gene-expression levels. Furthermore, H3K9me, but not perinuclear anchoring, also contributes to formation of another prominent feature of chromosome organization, megabase-scale topologically associating domains on X established by the dosage compensation condensin complex. Our results demonstrate that H3K9me plays crucial roles in regulating genome organization at multiple levels.


Assuntos
Caenorhabditis elegans/genética , Cromossomos/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Cromossomos/genética , Regulação da Expressão Gênica , Genoma , Heterocromatina/genética , Heterocromatina/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Lisina/genética , Metilação , Mutação , Cromossomo X/genética , Cromossomo X/metabolismo
9.
BMC Pregnancy Childbirth ; 22(1): 591, 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35879694

RESUMO

BACKGROUND: Establishing a healthy lifestyle post-delivery is pivotal to reduce the incidence of chronic diseases. Due to COVID-19 restrictions, access to postpartum health programs has been increasingly difficult. The aim of this study was to inform, develop and evaluate Beyond the Bump (BtB); an online program to improve access to health and wellbeing education and support for physical activity in the postpartum. METHODS: A three-phase mixed-methods design of a 10-week Australia-wide online pilot program during COVID-19 with women less than 1 year postpartum and their primary care health professionals was utilised. Phase-one: needs assessment focus groups and interviews. Phase-two: BtB program implementation pre-post health measures survey, attendance and engagement with the program. Phase-three: program evaluation with feedback surveys and interviews. RESULTS: Women (n = 12) and health professionals (n = 16) expressed strong need for a postpartum program with access to education from experts on exercise, pelvic floor, sleep and baby nutrition. Despite BtB being developed from women's suggestions (including time-of-day 'morning'), attendance to all ten sessions was poor (of 162 registrations; 23% participated in the first session and 5% in the last session). Barriers to attendance included 'too busy',' forgot' and 'topic not relevant for age of child'. 88% of women reported the education as the most enjoyable component of the program. 100% (n = 26) of women interviewed would recommend the program to a friend. CONCLUSIONS: There is a continuing need for postpartum support. Online programs with access to expert education and exercise were reported to be of significant interest and value. However, more research is needed to improve the uptake and value placed on mothers' wellbeing and physical activity.


Assuntos
COVID-19 , COVID-19/prevenção & controle , Criança , Feminino , Humanos , Estilo de Vida , Mães , Projetos Piloto , Período Pós-Parto
10.
Mar Drugs ; 20(8)2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-36005503

RESUMO

Seaweed polysaccharides in the diet may influence both inflammation and the gut microbiome. Here we describe two clinical studies with an Ulva sp. 84-derived sulfated polysaccharide­"xylorhamnoglucuronan" (SXRG84)­on metabolic markers, inflammation, and gut flora composition. The first study was a double-blind, randomized placebo-controlled trial with placebo, and either 2 g/day or 4 g/day of SXRG84 daily for six weeks in 64 overweight or obese participants (median age 55 years, median body mass index (BMI) 29 kg/m2). The second study was a randomized double-blind placebo-controlled crossover trial with 64 participants (median BMI 29 kg/m2, average age 52) on placebo for six weeks and then 2 g/day of SXRG84 treatment for six weeks, or vice versa. In Study 1, the 2 g/day dose exhibited a significant reduction in non-HDL (high-density lipoprotein) cholesterol (−10% or −0.37 mmol/L, p = 0.02) and in the atherogenic index (−50%, p = 0.05), and two-hour insulin (−12% or −4.83 mU/L) showed trends for reduction in overweight participants. CRP (C-reactive protein) was significantly reduced (−27% or −0.78 mg/L, p = 0.03) with the 4 g/day dose in overweight participants. Significant gut flora shifts included increases in Bifidobacteria, Akkermansia, Pseudobutyrivibrio, and Clostridium and a decrease in Bilophila. In Study 2, no significant differences in lipid measures were observed, but inflammatory cytokines were improved. At twelve weeks after the SXRG84 treatment, plasma cytokine concentrations were significantly lower than at six weeks post placebo for IFN-γ (3.4 vs. 7.3 pg/mL), IL-1ß (16.2 vs. 23.2 pg/mL), TNF-α (9.3 vs. 12.6 pg/mL), and IL-10 (1.6 vs. 2.1 pg/mL) (p < 0.05). Gut microbiota abundance and composition did not significantly differ between groups (p > 0.05). Together, the studies illustrate improvements in plasma lipids and an anti-inflammatory effect of dietary SXRG84 that is participant specific.


Assuntos
Microbiota , Sobrepeso , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Proteína C-Reativa , Pré-Escolar , HDL-Colesterol , Carboidratos da Dieta , Suplementos Nutricionais , Método Duplo-Cego , Humanos , Lactente , Inflamação/tratamento farmacológico , Pessoa de Meia-Idade , Sobrepeso/tratamento farmacológico , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Sulfatos
11.
PLoS Genet ; 15(7): e1008252, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31283754

RESUMO

The biological roles of nucleic acid methylation, other than at the C5-position of cytosines in CpG dinucleotides, are still not well understood. Here, we report genetic evidence for a critical role for the putative DNA demethylase NMAD-1 in regulating meiosis in C. elegans. nmad-1 mutants have reduced fertility. They show defects in prophase I of meiosis, which leads to reduced embryo production and an increased incidence of males due to defective chromosomal segregation. In nmad-1 mutant worms, nuclear staging beginning at the leptotene and zygotene stages is disorganized, the cohesin complex is mislocalized at the diplotene and diakinesis stages, and chromosomes are improperly condensed, fused, or lost by the end of diakinesis. RNA sequencing of the nmad-1 germline revealed reduced induction of DNA replication and DNA damage response genes during meiosis, which was coupled with delayed DNA replication, impaired DNA repair and increased apoptosis of maturing oocytes. To begin to understand how NMAD-1 regulates DNA replication and repair, we used immunoprecipitation and mass spectrometry to identify NMAD-1 binding proteins. NMAD-1 binds to multiple proteins that regulate DNA repair and replication, including topoisomerase TOP-2 and co-localizes with TOP-2 on chromatin. Moreover, the majority of TOP-2 binding to chromatin depends on NMAD-1. These results suggest that NMAD-1 functions at DNA replication sites to regulate DNA replication and repair during meiosis.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Reparo do DNA , Replicação do DNA , Dioxigenases/genética , Oxirredutases N-Desmetilantes/genética , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Segregação de Cromossomos , Dioxigenases/metabolismo , Masculino , Meiose , Mutação , Oxirredutases N-Desmetilantes/metabolismo , Análise de Sequência de RNA
12.
J Sport Rehabil ; 31(2): 199-210, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34784584

RESUMO

OBJECTIVES: Injury is a common and challenging experience for many athletes, and return-to-sport outcomes have been persistently poor despite advancements in research and practice. To ameliorate this challenge and to bridge a gap that exists in the sport injury literature between theoretical conceptualization and intervention design, research is needed to explore team-based approaches to professional practice. The current study aimed to begin this work through exploration of a single performance management team (PMT) through 2 injury and rehabilitation cases leading into and across the 2014 Olympic Winter Games. DESIGN: Qualitative, interpretative phenomenological analysis. METHOD: Interviews were conducted with the 5 members of the PMT (coach, physiotherapist, sport psychology consultant, case manager, and athlete) involved in both injury cases. Lower-order and higher order themes were identified and interpreted through the extent literature. RESULTS: Results indicate that 3 higher order themes interacted to impact the lived experiences of the PMT members across the 2 injury cases. Participants described the sociocultural context that surrounded the team, the individual struggles they faced, and the functioning of the team as the primary contributors to their lived experiences as well as observed rehabilitation outcomes. CONCLUSIONS: Findings of this study mirror previous research in team science within the general health care domain, and prompt ongoing exploration of how to improve the experiences for PMT members as well as rehabilitation and return-to-sport outcomes for athletes.


Assuntos
Fisioterapeutas , Esportes , Atletas , Humanos , Volta ao Esporte
13.
Nature ; 523(7559): 240-4, 2015 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-26030525

RESUMO

The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure. Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half. Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes. By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (∼1 Mb) resembling mammalian topologically associating domains (TADs). TADs on X chromosomes have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide.


Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/metabolismo , Mecanismo Genético de Compensação de Dose/fisiologia , Complexos Multiproteicos/metabolismo , Cromossomo X/metabolismo , Animais , Proteínas de Caenorhabditis elegans/genética , Mecanismo Genético de Compensação de Dose/genética , Feminino , Regulação da Expressão Gênica , Hibridização in Situ Fluorescente , Masculino , Ligação Proteica , Análise de Sequência de RNA , Cromossomo X/genética
14.
Genes Dev ; 27(10): 1159-78, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23666922

RESUMO

Sex is determined in Caenorhabditis elegans by the ratio of X chromosomes to the sets of autosomes, the X:A signal. A set of genes called X signal elements (XSEs) communicates X-chromosome dose by repressing the masculinizing sex determination switch gene xol-1 (XO lethal) in a dose-dependent manner. xol-1 is active in 1X:2A embryos (males) but repressed in 2X:2A embryos (hermaphrodites). Here we showed that the autosome dose is communicated by a set of autosomal signal elements (ASEs) that act in a cumulative, dose-dependent manner to counter XSEs by stimulating xol-1 transcription. We identified new ASEs and explored the biochemical basis by which ASEs antagonize XSEs to determine sex. Multiple antagonistic molecular interactions carried out on a single promoter explain how different X:A values elicit different sexual fates. XSEs (nuclear receptors and homeodomain proteins) and ASEs (T-box and zinc finger proteins) bind directly to several sites on xol-1 to counteract each other's activities and thereby regulate xol-1 transcription. Disrupting ASE- and XSE-binding sites in vivo recapitulated the misregulation of xol-1 transcription caused by disrupting cognate signal element genes. XSE- and ASE-binding sites are distinct and nonoverlapping, suggesting that direct competition for xol-1 binding is not how XSEs counter ASEs. Instead, XSEs likely antagonize ASEs by recruiting cofactors with reciprocal activities that induce opposite transcriptional states. Most ASE- and XSE-binding sites overlap xol-1's -1 nucleosome, which carries activating chromatin marks only when xol-1 is turned on. Coactivators and corepressors tethered by proteins similar to ASEs and XSEs are known to deposit and remove such marks. The concept of a sex signal comprising competing XSEs and ASEs arose as a theory for fruit flies a century ago. Ironically, while the recent work of others showed that the fly sex signal does not fit this simple paradigm, our work shows that the worm signal does.


Assuntos
Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/genética , Cromossomos/genética , Processos de Determinação Sexual/genética , Cromossomo X/genética , Motivos de Aminoácidos , Animais , Asparagina , Sítios de Ligação , Caenorhabditis elegans/embriologia , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Núcleo Celular/metabolismo , Elementos de DNA Transponíveis/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Mecanismo Genético de Compensação de Dose , Embrião não Mamífero/metabolismo , Feminino , Dosagem de Genes , Regulação da Expressão Gênica no Desenvolvimento/genética , Genes de Helmintos/genética , Glutamina , Proteínas de Homeodomínio/genética , Masculino , Regiões Promotoras Genéticas/genética , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Transcrição Gênica , Transposases/genética , Transposases/metabolismo
15.
Anaesthesist ; 70(7): 598-602, 2021 07.
Artigo em Alemão | MEDLINE | ID: mdl-33728478

RESUMO

Immune thrombozytopenia (ITP) is a rare acquired thrombocytopenia occurring in 2 to 4 persons per 100,000 per year. ITP is defined as a platelet count less than 100 G/l in patients in whom other causes of thrombocytopenia have been ruled out. Severe bleeding is rare but may constitute a life-threatening condition. Therapeutic options include platelet transfusions, glucocorticoids and intravenous immune globuline (IVIG). Emergency splenectomy has to be considered in otherwise untreatable bleeding. We present the case of a 65-year-old patient with chronic refractory ITP and finally fatal bleeding.


Assuntos
Púrpura Trombocitopênica Idiopática , Idoso , Tratamento de Emergência , Hemorragia/terapia , Humanos , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/terapia , Esplenectomia
16.
Br J Nutr ; 121(7): 793-808, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30688181

RESUMO

Numerous health benefits are attributed to the n-3 long-chain PUFA (n-3 LCPUFA); EPA and DHA. A systematic literature review was conducted to investigate factors, other than diet, that are associated with the n-3 LCPUFA levels. The inclusion criteria were papers written in English, carried out in adult non-pregnant humans, n-3 LCPUFA measured in blood or tissue, data from cross-sectional studies, or baseline data from intervention studies. The search revealed 5076 unique articles of which seventy were included in the qualitative synthesis. Three main groups of factors potentially associated with n-3 LCPUFA levels were identified: (1) unmodifiable factors (sex, genetics, age), (2) modifiable factors (body size, physical activity, alcohol, smoking) and (3) bioavailability factors (chemically bound form of supplements, krill oil v. fish oil, and conversion of plant-derived α-linolenic acid (ALA) to n-3 LCPUFA). Results showed that factors positively associated with n-3 LCPUFA levels were age, female sex (women younger than 50 years), wine consumption and the TAG form. Factors negatively associated with n-3 LCPUFA levels were genetics, BMI (if erythrocyte EPA and DHA levels are <5·6 %) and smoking. The evidence for girth, physical activity and krill oil v. fish oil associated with n-3 LCPUFA levels is inconclusive. There is also evidence that higher ALA consumption leads to increased levels of EPA but not DHA. In conclusion, sex, age, BMI, alcohol consumption, smoking and the form of n-3 LCPUFA are all factors that need to be taken into account in n-3 LCPUFA research.


Assuntos
Ácidos Graxos Ômega-3/sangue , Adulto , Fatores Etários , Consumo de Bebidas Alcoólicas/sangue , Índice de Massa Corporal , Feminino , Humanos , Masculino , Fatores Sexuais , Fumar/sangue
17.
Nature ; 502(7473): 703-6, 2013 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-24107990

RESUMO

Crossover recombination events between homologous chromosomes are required to form chiasmata, temporary connections between homologues that ensure their proper segregation at meiosis I. Despite this requirement for crossovers and an excess of the double-strand DNA breaks that are the initiating events for meiotic recombination, most organisms make very few crossovers per chromosome pair. Moreover, crossovers tend to inhibit the formation of other crossovers nearby on the same chromosome pair, a poorly understood phenomenon known as crossover interference. Here we show that the synaptonemal complex, a meiosis-specific structure that assembles between aligned homologous chromosomes, both constrains and is altered by crossover recombination events. Using a cytological marker of crossover sites in Caenorhabditis elegans, we show that partial depletion of the synaptonemal complex central region proteins attenuates crossover interference, increasing crossovers and reducing the effective distance over which interference operates, indicating that synaptonemal complex proteins limit crossovers. Moreover, we show that crossovers are associated with a local 0.4-0.5-micrometre increase in chromosome axis length. We propose that meiotic crossover regulation operates as a self-limiting system in which meiotic chromosome structures establish an environment that promotes crossover formation, which in turn alters chromosome structure to inhibit other crossovers at additional sites.


Assuntos
Caenorhabditis elegans/genética , Cromossomos/genética , Cromossomos/metabolismo , Troca Genética , Meiose , Animais , Caenorhabditis elegans/citologia , Proteínas de Caenorhabditis elegans/metabolismo , Pareamento Cromossômico , Segregação de Cromossomos , Cromossomos/química , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/metabolismo , Recombinação Homóloga , Meiose/genética , Proteínas Nucleares/deficiência , Proteínas Nucleares/metabolismo , Complexo Sinaptonêmico/metabolismo
18.
Nutr Neurosci ; 22(7): 474-487, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29215971

RESUMO

OBJECTIVES: We investigated whether a Mediterranean-style diet (MedDiet) supplemented with fish oil can improve mental health in adults suffering depression. METHODS: Adults with self-reported depression were randomized to receive fortnightly food hampers and MedDiet cooking workshops for 3 months and fish oil supplements for 6 months, or attend social groups fortnightly for 3 months. Assessments at baseline, 3 and 6 months included mental health, quality of life (QoL) and dietary questionnaires, and blood samples for erythrocyte fatty acid analysis. RESULTS: n = 152 eligible adults aged 18-65 were recruited (n = 95 completed 3-month and n = 85 completed 6-month assessments). At 3 months, the MedDiet group had a higher MedDiet score (t = 3.95, P < 0.01), consumed more vegetables (t = 3.95, P < 0.01), fruit (t = 2.10, P = 0.04), nuts (t = 2.29, P = 0.02), legumes (t = 2.41, P = 0.02) wholegrains (t = 2.63, P = 0.01), and vegetable diversity (t = 3.27, P < 0.01); less unhealthy snacks (t = -2.10, P = 0.04) and red meat/chicken (t = -2.13, P = 0.04). The MedDiet group had greater reduction in depression (t = -2.24, P = 0.03) and improved mental health QoL scores (t = 2.10, P = 0.04) at 3 months. Improved diet and mental health were sustained at 6 months. Reduced depression was correlated with an increased MedDiet score (r = -0.298, P = 0.01), nuts (r = -0.264, P = 0.01), and vegetable diversity (r = -0.303, P = 0.01). Other mental health improvements had similar correlations, most notably for increased vegetable diversity and legumes. There were some correlations between increased omega-3, decreased omega-6 and improved mental health. DISCUSSION: This is one of the first randomized controlled trials to show that healthy dietary changes are achievable and, supplemented with fish oil, can improve mental health in people with depression.


Assuntos
Depressão/dietoterapia , Depressão/psicologia , Dieta Mediterrânea , Óleos de Peixe/administração & dosagem , Saúde Mental , Adolescente , Adulto , Idoso , Depressão/sangue , Suplementos Nutricionais , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do Tratamento , Adulto Jovem
20.
Genes Dev ; 25(5): 499-515, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21363964

RESUMO

Here we analyze the essential process of X-chromosome dosage compensation (DC) to elucidate mechanisms that control the assembly, genome-wide binding, and function of gene regulatory complexes that act over large chromosomal territories. We demonstrate that a subunit of Caenorhabditis elegans MLL/COMPASS, a gene activation complex, acts within the DC complex (DCC), a condensin complex, to target the DCC to both X chromosomes of hermaphrodites for chromosome-wide reduction of gene expression. The DCC binds to two categories of sites on X: rex (recruitment element on X) sites that recruit the DCC in an autonomous, sequence-dependent manner, and dox (dependent on X) sites that reside primarily in promoters of expressed genes and bind the DCC robustly only when attached to X. We find that DC mutations that abolish rex site binding greatly reduce dox site binding but do not eliminate it. Instead, binding is diminished to the low level observed at autosomal sites in wild-type animals. Changes in DCC binding to these non-rex sites occur throughout development and correlate directly with transcriptional activity of adjacent genes. Moreover, autosomal DCC binding is enhanced by rex site binding in cis in X-autosome fusion chromosomes. Thus, dox and autosomal sites have similar binding potential but are distinguished by linkage to rex sites. We propose a model for DCC binding in which low-level DCC binding at dox sites is dictated by intrinsic properties correlated with high transcriptional activity. Sex-specific DCC recruitment to rex sites then enhances the magnitude of DCC binding to dox sites in cis, which lack high affinity for the DCC on their own. We also show that the DCC balances X-chromosome gene expression between sexes by controlling transcription.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Mecanismo Genético de Compensação de Dose/genética , Regulação da Expressão Gênica , Adenosina Trifosfatases/metabolismo , Animais , Proteínas de Ligação a DNA/metabolismo , Feminino , Genoma Helmíntico/genética , Masculino , Complexos Multiproteicos/metabolismo , Mutação , Proteínas Nucleares , Ligação Proteica , Subunidades Proteicas/metabolismo , Cromossomo X/genética , Cromossomo X/metabolismo
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