Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
Genome Res ; 32(3): 474-487, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35045977

RESUMO

The chromatin environment plays a central role in regulating developmental gene expression in metazoans. Yet, the ancestral regulatory landscape of metazoan embryogenesis is unknown. Here, we generate chromatin accessibility profiles for six embryonic, plus larval and adult stages in the sponge Amphimedon queenslandica These profiles are reproducible within stages, reflect histone modifications, and identify transcription factor (TF) binding sequence motifs predictive of cis-regulatory elements operating during embryogenesis in other metazoans, but not the unicellular relative Capsaspora Motif analysis of chromatin accessibility profiles across Amphimedon embryogenesis identifies three major developmental periods. As in bilaterian embryogenesis, early development in Amphimedon involves activating and repressive chromatin in regions both proximal and distal to transcription start sites. Transcriptionally repressive elements ("silencers") are prominent during late embryogenesis. They coincide with an increase in cis-regulatory regions harboring metazoan TF binding motifs, as well as an increase in the expression of metazoan-specific genes. Changes in chromatin state and gene expression in Amphimedon suggest the conservation of distal enhancers, dynamically silenced chromatin, and TF-DNA binding specificity in animal embryogenesis.


Assuntos
Cromatina , Código das Histonas , Animais , Cromatina/genética , DNA/metabolismo , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Ligação Proteica
2.
Blood ; 142(17): 1448-1462, 2023 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-37595278

RESUMO

Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay among transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs (FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2) bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remains unknown. We mapped genome-wide chromatin contacts (HiC, H3K27ac, HiChIP), chromatin modifications (H3K4me3, H3K27ac, H3K27me3) and 10 TF binding profiles (heptad, PU.1, CTCF, STAG2) in HSPC subsets (stem/multipotent progenitors plus common myeloid, granulocyte macrophage, and megakaryocyte erythrocyte progenitors) and found TF occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. Furthermore, heptad-occupied regions in HSPCs were subsequently bound by lineage-defining TFs, including PU.1 and GATA1, suggesting that heptad factors may prime regulatory elements for use in mature cell types. We also found that enhancers with cell-type-specific heptad occupancy shared a common grammar with respect to TF binding motifs, suggesting that combinatorial binding of TF complexes was at least partially regulated by features encoded in DNA sequence motifs. Taken together, this study comprehensively characterizes the gene regulatory landscape in rare subpopulations of human HSPCs. The accompanying data sets should serve as a valuable resource for understanding adult hematopoiesis and a framework for analyzing aberrant regulatory networks in leukemic cells.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Células-Tronco Hematopoéticas , Humanos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Regulação da Expressão Gênica , Hematopoese/genética , Cromatina/metabolismo
3.
BMC Evol Biol ; 20(1): 103, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807071

RESUMO

BACKGROUND: Vertebrates exhibit diverse sex determination systems and reptiles stand out by having highly variable sex determinations that include temperature-dependent and genotypic sex determination (TSD and GSD, respectively). Theory predicts that populations living in either highly variable or cold climatic conditions should evolve genotypic sex determination to buffer the populations from extreme sex ratios, yet these fundamental predictions have not been tested across a wide range of taxa. RESULTS: Here, we use phylogenetic analyses of 213 reptile species representing 38 families (TSD = 101 species, GSD = 112 species) and climatic data to compare breeding environments between reptiles with GSD versus TSD. We show that GSD and TSD are confronted with the same level of climatic fluctuation during breeding seasons. However, TSD reptiles are significantly associated with warmer climates. We found a strong selection on the breeding season length that minimises exposure to cold and fluctuating climate. Phylogenetic path analyses comparing competing evolutionary hypotheses support that transitions in sex determination systems influenced the ambient temperature at which the species reproduces and nests. In turn, this interaction affects other variables such as the duration of the breeding season and life-history traits. CONCLUSIONS: Taken together, our results challenge long-standing hypotheses about the association between sex determination and climate variability. We also show that ambient temperature is important during breeding seasons and it helps explain the effects of sex determination systems on the geographic distribution of extant reptile species.


Assuntos
Clima , Répteis/fisiologia , Processos de Determinação Sexual , Temperatura , Animais , Cruzamento , Filogenia , Répteis/genética , Processos de Determinação Sexual/genética , Razão de Masculinidade
4.
Nat Commun ; 15(1): 3451, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38658544

RESUMO

Enhancers are fast-evolving genomic sequences that control spatiotemporal gene expression patterns. By examining enhancer turnover across mammalian species and in multiple tissue types, we uncover a relationship between the emergence of enhancers and genome organization as a function of germline DNA replication time. While enhancers are most abundant in euchromatic regions, enhancers emerge almost twice as often in late compared to early germline replicating regions, independent of transposable elements. Using a deep learning sequence model, we demonstrate that new enhancers are enriched for mutations that alter transcription factor (TF) binding. Recently evolved enhancers appear to be mostly neutrally evolving and enriched in eQTLs. They also show more tissue specificity than conserved enhancers, and the TFs that bind to these elements, as inferred by binding sequences, also show increased tissue-specific gene expression. We find a similar relationship with DNA replication time in cancer, suggesting that these observations may be time-invariant principles of genome evolution. Our work underscores that genome organization has a profound impact in shaping mammalian gene regulation.


Assuntos
Replicação do DNA , Elementos Facilitadores Genéticos , Animais , Humanos , Evolução Molecular , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Camundongos , Regulação da Expressão Gênica , Especificidade de Órgãos/genética , Mutação , Genoma/genética , Elementos de DNA Transponíveis/genética
5.
Genome Biol ; 24(1): 116, 2023 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-37173718

RESUMO

Enhancers are genomic DNA elements controlling spatiotemporal gene expression. Their flexible organization and functional redundancies make deciphering their sequence-function relationships challenging. This article provides an overview of the current understanding of enhancer organization and evolution, with an emphasis on factors that influence these relationships. Technological advancements, particularly in machine learning and synthetic biology, are discussed in light of how they provide new ways to understand this complexity. Exciting opportunities lie ahead as we continue to unravel the intricacies of enhancer function.


Assuntos
DNA , Elementos Facilitadores Genéticos , DNA/metabolismo , Aprendizado de Máquina
6.
Elife ; 122023 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-37272612

RESUMO

Unlike single-gene mutations leading to Mendelian conditions, common human diseases are likely to be emergent phenomena arising from multilayer, multiscale, and highly interconnected interactions. Atrial and ventricular septal defects are the most common forms of cardiac congenital anomalies in humans. Atrial septal defects (ASD) show an open communication between the left and right atria postnatally, potentially resulting in serious hemodynamic consequences if untreated. A milder form of atrial septal defect, patent foramen ovale (PFO), exists in about one-quarter of the human population, strongly associated with ischaemic stroke and migraine. The anatomic liabilities and genetic and molecular basis of atrial septal defects remain unclear. Here, we advance our previous analysis of atrial septal variation through quantitative trait locus (QTL) mapping of an advanced intercross line (AIL) established between the inbred QSi5 and 129T2/SvEms mouse strains, that show extremes of septal phenotypes. Analysis resolved 37 unique septal QTL with high overlap between QTL for distinct septal traits and PFO as a binary trait. Whole genome sequencing of parental strains and filtering identified predicted functional variants, including in known human congenital heart disease genes. Transcriptome analysis of developing septa revealed downregulation of networks involving ribosome, nucleosome, mitochondrial, and extracellular matrix biosynthesis in the 129T2/SvEms strain, potentially reflecting an essential role for growth and cellular maturation in septal development. Analysis of variant architecture across different gene features, including enhancers and promoters, provided evidence for the involvement of non-coding as well as protein-coding variants. Our study provides the first high-resolution picture of genetic complexity and network liability underlying common congenital heart disease, with relevance to human ASD and PFO.


Assuntos
Isquemia Encefálica , Forame Oval Patente , Cardiopatias Congênitas , Acidente Vascular Cerebral , Humanos , Camundongos , Animais , Forame Oval Patente/genética , Fenótipo , Perfilação da Expressão Gênica
7.
Commun Biol ; 4(1): 1418, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34934158

RESUMO

Mosaic loss of the Y chromosome (LOY) is the most frequent chromosomal aberration in aging men and is strongly correlated with mortality and disease. To date, studies of LOY have only been performed in humans, and so it is unclear whether LOY is a natural consequence of our relatively long lifespan or due to exposure to human-specific external stressors. Here, we explored whether LOY could be detected in rats. We applied a locus-specific PCR and target sequencing approach that we used as a proxy to estimate LOY in 339 samples covering eleven tissues from young and old individuals. We detected LOY in four tissues of older rats. To confirm the results from the PCR screening, we re-sequenced 60 full genomes from old rats, which revealed that the Y chromosome is the sole chromosome with low copy numbers. Finally, our results suggest that LOY is associated with other structural aberrations on the Y chromosome and possibly linked to the mosaic loss of the X chromosome. This is the first report, to our knowledge, demonstrating that the patterns of LOY observed in aging men are also present in a rodent, and conclude that LOY may be a natural process in placental mammals.


Assuntos
Envelhecimento/genética , Variação Genética , Monossomia , Cromossomo Y/patologia , Fatores Etários , Animais , Masculino , Ratos , Ratos Wistar
8.
Genome Biol Evol ; 12(11): 2015-2028, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-32790864

RESUMO

Placental mammals present 180 million-year-old Y chromosomes that have retained a handful of dosage-sensitive genes. However, the expression evolution of Y-linked genes across placental groups has remained largely unexplored. Here, we expanded the number of Y gametolog sequences by analyzing ten additional species from previously unexplored groups. We detected seven remarkably conserved genes across 25 placental species with known Y repertoires. We then used RNA-seq data from 17 placental mammals to unveil the expression evolution of XY gametologs. We found that Y gametologs followed, on average, a 3-fold expression loss and that X gametologs also experienced some expression reduction, particularly in primates. Y gametologs gained testis specificity through an accelerated expression decay in somatic tissues. Moreover, despite the substantial expression decay of Y genes, the combined expression of XY gametologs in males is higher than that of both X gametologs in females. Finally, our work describes several features of the Y chromosome in the last common mammalian ancestor.


Assuntos
Evolução Biológica , Eutérios/genética , Expressão Gênica , Genes Ligados ao Cromossomo X , Genes Ligados ao Cromossomo Y , Animais , Sequência de Bases , Sequência Conservada , Mecanismo Genético de Compensação de Dose , Feminino , Humanos , Masculino , Especificidade de Órgãos
9.
Genome Biol Evol ; 12(6): 924-930, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32433751

RESUMO

The water skinks Eulamprus tympanum and Eulamprus heatwolei show thermally induced sex determination where elevated temperatures give rise to male offspring. Paradoxically, Eulamprus species reproduce in temperatures of 12-15 °C making them outliers when compared with reptiles that use temperature as a cue for sex determination. Moreover, these two species are among the very few viviparous reptiles reported to have thermally induced sex determination. Thus, we tested whether these skinks possess undetected sex chromosomes with thermal override. We produced transcriptome and genome data for E. heatwolei. We found that E. heatwolei presents XY chromosomes that include 14 gametologs with regulatory functions. The Y chromosomal region is 79-116 Myr old and shared between water and spotted skinks. Our work provides clear evidence that climate could be useful to predict the type of sex determination systems in reptiles and it also indicates that viviparity is strictly associated with sex chromosomes.


Assuntos
Lagartos/genética , Cromossomos Sexuais , Processos de Determinação Sexual , Viviparidade não Mamífera/genética , Animais , Feminino , Masculino
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA