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1.
Nature ; 620(7975): 863-872, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37587336

RESUMO

Cells undergo a major epigenome reconfiguration when reprogrammed to human induced pluripotent stem cells (hiPS cells). However, the epigenomes of hiPS cells and human embryonic stem (hES) cells differ significantly, which affects hiPS cell function1-8. These differences include epigenetic memory and aberrations that emerge during reprogramming, for which the mechanisms remain unknown. Here we characterized the persistence and emergence of these epigenetic differences by performing genome-wide DNA methylation profiling throughout primed and naive reprogramming of human somatic cells to hiPS cells. We found that reprogramming-induced epigenetic aberrations emerge midway through primed reprogramming, whereas DNA demethylation begins early in naive reprogramming. Using this knowledge, we developed a transient-naive-treatment (TNT) reprogramming strategy that emulates the embryonic epigenetic reset. We show that the epigenetic memory in hiPS cells is concentrated in cell of origin-dependent repressive chromatin marked by H3K9me3, lamin-B1 and aberrant CpH methylation. TNT reprogramming reconfigures these domains to a hES cell-like state and does not disrupt genomic imprinting. Using an isogenic system, we demonstrate that TNT reprogramming can correct the transposable element overexpression and differential gene expression seen in conventional hiPS cells, and that TNT-reprogrammed hiPS and hES cells show similar differentiation efficiencies. Moreover, TNT reprogramming enhances the differentiation of hiPS cells derived from multiple cell types. Thus, TNT reprogramming corrects epigenetic memory and aberrations, producing hiPS cells that are molecularly and functionally more similar to hES cells than conventional hiPS cells. We foresee TNT reprogramming becoming a new standard for biomedical and therapeutic applications and providing a novel system for studying epigenetic memory.


Assuntos
Reprogramação Celular , Epigênese Genética , Células-Tronco Pluripotentes Induzidas , Humanos , Cromatina/genética , Cromatina/metabolismo , Desmetilação do DNA , Metilação de DNA , Elementos de DNA Transponíveis , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Embrionárias Humanas/metabolismo , Lamina Tipo B
2.
Nature ; 587(7834): 455-459, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33116314

RESUMO

Reproduction induces increased food intake across females of many animal species1-4, providing a physiologically relevant paradigm for the exploration of appetite regulation. Here, by examining the diversity of enteric neurons in Drosophila melanogaster, we identify a key role for gut-innervating neurons with sex- and reproductive state-specific activity in sustaining the increased food intake of mothers during reproduction. Steroid and enteroendocrine hormones functionally remodel these neurons, which leads to the release of their neuropeptide onto the muscles of the crop-a stomach-like organ-after mating. Neuropeptide release changes the dynamics of crop enlargement, resulting in increased food intake, and preventing the post-mating remodelling of enteric neurons reduces both reproductive hyperphagia and reproductive fitness. The plasticity of enteric neurons is therefore key to reproductive success. Our findings provide a mechanism to attain the positive energy balance that sustains gestation, dysregulation of which could contribute to infertility or weight gain.


Assuntos
Drosophila melanogaster/citologia , Drosophila melanogaster/fisiologia , Ingestão de Alimentos/fisiologia , Ingestão de Energia/fisiologia , Mães , Neurônios/metabolismo , Reprodução/fisiologia , Estruturas Animais/citologia , Estruturas Animais/inervação , Estruturas Animais/metabolismo , Animais , Regulação do Apetite/fisiologia , Feminino , Hiperfagia/metabolismo , Masculino , Neuropeptídeos/metabolismo
3.
J Biol Chem ; 298(10): 102462, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36067881

RESUMO

Specific DNA methylation at CpG and non-CpG sites is essential for chromatin regulation. The DNA methyltransferase DNMT3A interacts with target sites surrounded by variable DNA sequences with its TRD and RD loops, but the functional necessity of these interactions is unclear. We investigated CpG and non-CpG methylation in a randomized sequence context using WT DNMT3A and several DNMT3A variants containing mutations at DNA-interacting residues. Our data revealed that the flanking sequence of target sites between the -2 and up to the +8 position modulates methylation rates >100-fold. Non-CpG methylation flanking preferences were even stronger and favor C(+1). R836 and N838 in concert mediate recognition of the CpG guanine. R836 changes its conformation in a flanking sequence-dependent manner and either contacts the CpG guanine or the +1/+2 flank, thereby coupling the interaction with both sequence elements. R836 suppresses activity at CNT sites but supports methylation of CAC substrates, the preferred target for non-CpG methylation of DNMT3A in cells. N838 helps to balance this effect and prevent the preference for C(+1) from becoming too strong. Surprisingly, we found L883 reduces DNMT3A activity despite being highly conserved in evolution. However, mutations at L883 disrupt the DNMT3A-specific DNA interactions of the RD loop, leading to altered flanking sequence preferences. Similar effects occur after the R882H mutation in cancer cells. Our data reveal that DNMT3A forms flexible and interdependent interaction networks with the CpG guanine and flanking residues that ensure recognition of the CpG and efficient methylation of the cytosine in contexts of variable flanking sequences.


Assuntos
Metilação de DNA , DNA Metiltransferase 3A , Ilhas de CpG , DNA/química , DNA/metabolismo , Metilases de Modificação do DNA/genética , Guanina , Mutação
4.
Development ; 147(23)2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33272929

RESUMO

Almost all animals undergo embryonic development, going from a single-celled zygote to a complex multicellular adult. We know that the patterning and morphogenetic processes involved in development are deeply conserved within the animal kingdom. However, the origins of these developmental processes are just beginning to be unveiled. Here, we focus on how the protist lineages sister to animals are reshaping our view of animal development. Most intriguingly, many of these protistan lineages display transient multicellular structures, which are governed by similar morphogenetic and gene regulatory processes as animal development. We discuss here two potential alternative scenarios to explain the origin of animal embryonic development: either it originated concomitantly at the onset of animals or it evolved from morphogenetic processes already present in their unicellular ancestors. We propose that an integrative study of several unicellular taxa closely related to animals will allow a more refined picture of how the last common ancestor of animals underwent embryonic development.


Assuntos
Evolução Biológica , Coanoflagelados/crescimento & desenvolvimento , Desenvolvimento Embrionário/genética , Morfogênese/genética , Animais , Coanoflagelados/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Mamíferos/genética , Filogenia , Zigoto/crescimento & desenvolvimento
5.
Genome Res ; 29(8): 1277-1286, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31239280

RESUMO

The repressive capacity of cytosine DNA methylation is mediated by recruitment of silencing complexes by methyl-CpG binding domain (MBD) proteins. Despite MBD proteins being associated with silencing, we discovered that a family of arthropod Copia retrotransposons have incorporated a host-derived MBD. We functionally show how retrotransposon-encoded MBDs preferentially bind to CpG-dense methylated regions, which correspond to transposable element regions of the host genome, in the myriapod Strigamia maritima Consistently, young MBD-encoding Copia retrotransposons (CopiaMBD) accumulate in regions with higher CpG densities than other LTR-retrotransposons also present in the genome. This would suggest that retrotransposons use MBDs to integrate into heterochromatic regions in Strigamia, avoiding potentially harmful insertions into host genes. In contrast, CopiaMBD insertions in the spider Stegodyphus dumicola genome disproportionately accumulate in methylated gene bodies compared with other spider LTR-retrotransposons. Given that transposons are not actively targeted by DNA methylation in the spider genome, this distribution bias would also support a role for MBDs in the integration process. Together, these data show that retrotransposons can co-opt host-derived epigenome readers, potentially harnessing the host epigenome landscape to advantageously tune the retrotransposition process.


Assuntos
Artrópodes/genética , Ilhas de CpG , Proteínas de Ligação a DNA/genética , Genoma , Retroelementos , Sequência de Aminoácidos , Animais , Artrópodes/classificação , Artrópodes/metabolismo , Citosina/metabolismo , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Filogenia , Domínios Proteicos , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade da Espécie
6.
Nucleic Acids Res ; 48(22): 12675-12688, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33271598

RESUMO

In vertebrates, DNA methylation predominantly occurs at CG dinucleotides however, widespread non-CG methylation (mCH) has been reported in mammalian embryonic stem cells and in the brain. In mammals, mCH is found at CAC trinucleotides in the nervous system, where it is associated with transcriptional repression, and at CAG trinucleotides in embryonic stem cells, where it positively correlates with transcription. Moreover, CAC methylation appears to be a conserved feature of adult vertebrate brains. Unlike any of those methylation signatures, here we describe a novel form of mCH that occurs in the TGCT context within zebrafish mosaic satellite repeats. TGCT methylation is inherited from both male and female gametes, remodelled during mid-blastula transition, and re-established during gastrulation in all embryonic layers. Moreover, we identify DNA methyltransferase 3ba (Dnmt3ba) as the primary enzyme responsible for the deposition of this mCH mark. Finally, we observe that TGCT-methylated repeats are specifically associated with H3K9me3-marked heterochromatin suggestive of a functional interplay between these two gene-regulatory marks. Altogether, this work provides insight into a novel form of vertebrate mCH and highlights the substrate diversity of vertebrate DNA methyltransferases.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/genética , DNA Satélite/genética , Processamento de Proteína Pós-Traducional/genética , Proteínas de Peixe-Zebra/genética , Animais , Blastocisto/metabolismo , Células-Tronco Embrionárias/metabolismo , Heterocromatina , Histonas/genética , Mosaicismo , Sequências Repetitivas de Ácido Nucleico/genética , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
8.
Proc Natl Acad Sci U S A ; 113(10): 2684-9, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26903629

RESUMO

Molecular fossils (or biomarkers) are key to unraveling the deep history of eukaryotes, especially in the absence of traditional fossils. In this regard, the sterane 24-isopropylcholestane has been proposed as a molecular fossil for sponges, and could represent the oldest evidence for animal life. The sterane is found in rocks ∼650-540 million y old, and its sterol precursor (24-isopropylcholesterol, or 24-ipc) is synthesized today by certain sea sponges. However, 24-ipc is also produced in trace amounts by distantly related pelagophyte algae, whereas only a few close relatives of sponges have been assayed for sterols. In this study, we analyzed the sterol and gene repertoires of four taxa (Salpingoeca rosetta, Capsaspora owczarzaki, Sphaeroforma arctica, and Creolimax fragrantissima), which collectively represent the major living animal outgroups. We discovered that all four taxa lack C30 sterols, including 24-ipc. By building phylogenetic trees for key enzymes in 24-ipc biosynthesis, we identified a candidate gene (carbon-24/28 sterol methyltransferase, or SMT) responsible for 24-ipc production. Our results suggest that pelagophytes and sponges independently evolved C30 sterol biosynthesis through clade-specific SMT duplications. Using a molecular clock approach, we demonstrate that the relevant sponge SMT duplication event overlapped with the appearance of 24-isopropylcholestanes in the Neoproterozoic, but that the algal SMT duplication event occurred later in the Phanerozoic. Subsequently, pelagophyte algae and their relatives are an unlikely alternative to sponges as a source of Neoproterozoic 24-isopropylcholestanes, consistent with growing evidence that sponges evolved long before the Cambrian explosion ∼542 million y ago.


Assuntos
Biomarcadores/metabolismo , Genômica/métodos , Poríferos/genética , Esteróis/biossíntese , Animais , Biomarcadores/química , Desidrocolesteróis/análise , Desidrocolesteróis/química , Desidrocolesteróis/metabolismo , Evolução Molecular , Duplicação Gênica , Metiltransferases/química , Metiltransferases/genética , Metiltransferases/metabolismo , Modelos Moleculares , Estrutura Molecular , Filogenia , Poríferos/classificação , Poríferos/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Especificidade da Espécie , Esteróis/análise , Esteróis/química , Fatores de Tempo
9.
Proc Natl Acad Sci U S A ; 110(50): E4858-66, 2013 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-24277850

RESUMO

Transcription factors (TFs) are the main players in transcriptional regulation in eukaryotes. However, it remains unclear what role TFs played in the origin of all of the different eukaryotic multicellular lineages. In this paper, we explore how the origin of TF repertoires shaped eukaryotic evolution and, in particular, their role into the emergence of multicellular lineages. We traced the origin and expansion of all known TFs through the eukaryotic tree of life, using the broadest possible taxon sampling and an updated phylogenetic background. Our results show that the most complex multicellular lineages (i.e., those with embryonic development, Metazoa and Embryophyta) have the most complex TF repertoires, and that these repertoires were assembled in a stepwise manner. We also show that a significant part of the metazoan and embryophyte TF toolkits evolved earlier, in their respective unicellular ancestors. To gain insights into the role of TFs in the development of both embryophytes and metazoans, we analyzed TF expression patterns throughout their ontogeny. The expression patterns observed in both groups recapitulate those of the whole transcriptome, but reveal some important differences. Our comparative genomics and expression data reshape our view on how TFs contributed to eukaryotic evolution and reveal the importance of TFs to the origins of multicellularity and embryonic development.


Assuntos
Diferenciação Celular/genética , Desenvolvimento Embrionário/genética , Eucariotos/genética , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento/genética , Fatores de Transcrição/genética , Biologia Computacional , Genômica/métodos , Estatísticas não Paramétricas
10.
J Exp Bot ; 65(10): 2657-66, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24323507

RESUMO

The retinoblastoma (Rb) protein was identified as a human tumour suppressor protein that controls various stages of cell proliferation through the interaction with members of the E2F family of transcription factors. It was originally thought to be specific to animals but plants contain homologues of Rb, called RETINOBLASTOMA-RELATED (RBR). In fact, the Rb-E2F module seems to be a very early acquisition of eukaryotes. The activity of RBR depends on phosphorylation of certain amino acid residues, which in most cases are well conserved between plant and animal proteins. In addition to its role in cell-cycle progression, RBR has been shown to participate in various cellular processes such as endoreplication, transcriptional regulation, chromatin remodelling, cell growth, stem cell biology, and differentiation. Here, we discuss the most recent advances to define the role of RBR in cell proliferation and asymmetric cell division. These and other reports clearly support the idea that RBR is used as a landing platform of a plethora of cellular proteins and complexes to control various aspects of cell physiology and plant development.


Assuntos
Proteínas de Arabidopsis/fisiologia , Divisão Celular , Proliferação de Células , Plantas/metabolismo , Proteínas de Arabidopsis/genética , Ciclo Celular , Regulação da Expressão Gênica de Plantas , Células Vegetais
11.
Commun Biol ; 7(1): 582, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38755427

RESUMO

The DNA methyltransferase DNMT3C appeared as a duplication of the DNMT3B gene in muroids and is required for silencing of young retrotransposons in the male germline. Using specialized assay systems, we investigate the flanking sequence preferences of DNMT3C and observe characteristic preferences for cytosine at the -2 and -1 flank that are unique among DNMT3 enzymes. We identify two amino acids in the catalytic domain of DNMT3C (C543 and V547) that are responsible for the DNMT3C-specific flanking sequence preferences and evolutionary conserved in muroids. Reanalysis of published data shows that DNMT3C flanking preferences are consistent with genome-wide methylation patterns in mouse ES cells only expressing DNMT3C. Strikingly, we show that CpG sites with the preferred flanking sequences of DNMT3C are enriched in murine retrotransposons that were previously identified as DNMT3C targets. Finally, we demonstrate experimentally that DNMT3C has elevated methylation activity on substrates derived from these biological targets. Our data show that DNMT3C flanking sequence preferences match the sequences of young murine retrotransposons which facilitates their methylation. By this, our data provide mechanistic insights into the molecular co-evolution of repeat elements and (epi)genetic defense systems dedicated to maintain genomic stability in mammals.


Assuntos
DNA (Citosina-5-)-Metiltransferases , Metilação de DNA , Retroelementos , Animais , Camundongos , Ilhas de CpG , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Retroelementos/genética
12.
Sci Adv ; 10(28): eado6406, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38996012

RESUMO

5-Methylcytosine (5mC) is a widespread silencing mechanism that controls genomic parasites. In eukaryotes, 5mC has gained complex roles in gene regulation beyond parasite control, yet 5mC has also been lost in many lineages. The causes for 5mC retention and its genomic consequences are still poorly understood. Here, we show that the protist closely related to animals Amoebidium appalachense features both transposon and gene body methylation, a pattern reminiscent of invertebrates and plants. Unexpectedly, hypermethylated genomic regions in Amoebidium derive from viral insertions, including hundreds of endogenized giant viruses, contributing 14% of the proteome. Using a combination of inhibitors and genomic assays, we demonstrate that 5mC silences these giant virus insertions. Moreover, alternative Amoebidium isolates show polymorphic giant virus insertions, highlighting a dynamic process of infection, endogenization, and purging. Our results indicate that 5mC is critical for the controlled coexistence of newly acquired viral DNA into eukaryotic genomes, making Amoebidium a unique model to understand the hybrid origins of eukaryotic DNA.


Assuntos
Metilação de DNA , Vírus Gigantes , Animais , Vírus Gigantes/genética , 5-Metilcitosina/metabolismo , Elementos de DNA Transponíveis/genética , DNA Viral/genética
13.
Genome Biol ; 25(1): 204, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39090757

RESUMO

BACKGROUND: DNA methylation in the form of 5-methylcytosine (5mC) is the most abundant base modification in animals. However, 5mC levels vary widely across taxa. While vertebrate genomes are hypermethylated, in most invertebrates, 5mC concentrates on constantly and highly transcribed genes (gene body methylation; GbM) and, in some species, on transposable elements (TEs), a pattern known as "mosaic". Yet, the role and developmental dynamics of 5mC and how these explain interspecies differences in DNA methylation patterns remain poorly understood, especially in Spiralia, a large clade of invertebrates comprising nearly half of the animal phyla. RESULTS: Here, we generate base-resolution methylomes for three species with distinct genomic features and phylogenetic positions in Annelida, a major spiralian phylum. All possible 5mC patterns occur in annelids, from typical invertebrate intermediate levels in a mosaic distribution to hypermethylation and methylation loss. GbM is common to annelids with 5mC, and methylation differences across species are explained by taxon-specific transcriptional dynamics or the presence of intronic TEs. Notably, the link between GbM and transcription decays during development, alongside a gradual and global, age-dependent demethylation in adult stages. Additionally, reducing 5mC levels with cytidine analogs during early development impairs normal embryogenesis and reactivates TEs in the annelid Owenia fusiformis. CONCLUSIONS: Our study indicates that global epigenetic erosion during development and aging is an ancestral feature of bilateral animals. However, the tight link between transcription and gene body methylation is likely more important in early embryonic stages, and 5mC-mediated TE silencing probably emerged convergently across animal lineages.


Assuntos
Envelhecimento , Metilação de DNA , Epigênese Genética , Animais , Envelhecimento/genética , Anelídeos/genética , Filogenia , Epigenoma , 5-Metilcitosina/metabolismo , Elementos de DNA Transponíveis , Evolução Molecular
14.
Nat Ecol Evol ; 8(3): 519-535, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38216617

RESUMO

Polyploidy or whole-genome duplication (WGD) is a major event that drastically reshapes genome architecture and is often assumed to be causally associated with organismal innovations and radiations. The 2R hypothesis suggests that two WGD events (1R and 2R) occurred during early vertebrate evolution. However, the timing of the 2R event relative to the divergence of gnathostomes (jawed vertebrates) and cyclostomes (jawless hagfishes and lampreys) is unresolved and whether these WGD events underlie vertebrate phenotypic diversification remains elusive. Here we present the genome of the inshore hagfish, Eptatretus burgeri. Through comparative analysis with lamprey and gnathostome genomes, we reconstruct the early events in cyclostome genome evolution, leveraging insights into the ancestral vertebrate genome. Genome-wide synteny and phylogenetic analyses support a scenario in which 1R occurred in the vertebrate stem-lineage during the early Cambrian, and 2R occurred in the gnathostome stem-lineage, maximally in the late Cambrian-earliest Ordovician, after its divergence from cyclostomes. We find that the genome of stem-cyclostomes experienced an additional independent genome triplication. Functional genomic and morphospace analyses demonstrate that WGD events generally contribute to developmental evolution with similar changes in the regulatory genome of both vertebrate groups. However, appreciable morphological diversification occurred only in the gnathostome but not in the cyclostome lineage, calling into question the general expectation that WGDs lead to leaps of bodyplan complexity.


Assuntos
Feiticeiras (Peixe) , Animais , Filogenia , Feiticeiras (Peixe)/genética , Duplicação Gênica , Vertebrados/genética , Genoma , Lampreias/genética
15.
Science ; 381(6658): 602-603, 2023 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-37561871

RESUMO

A study of 348 species offers clues into the diversity of mammalian life spans.


Assuntos
Metilação de DNA , Longevidade , Mamíferos , Animais , Mamíferos/genética , Longevidade/genética
16.
Mol Biol Evol ; 28(11): 2987-91, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21616910

RESUMO

Phylogenomic analyses have revealed several important metazoan clades, such as the Ecdysozoa and the Lophotrochozoa. However, the phylogenetic positions of a few taxa, such as ctenophores, chaetognaths, acoelomorphs, and Xenoturbella, remain contentious. Thus, the findings of qualitative markers or "rare genomic changes" seem ideal to independently test previous phylogenetic hypotheses. We here describe a rare genomic change, the presence of the gene UDP-GlcNAc 2-epimerase/N-acetylmannosamine kinase (GNE). We show that GNE is encoded in the genomes of deuterostomes, acoelomorphs and Xenoturbella, whereas it is absent in protostomes and nonbilaterians. Moreover, the GNE has a complex evolutionary origin involving unique lateral gene transfer events and/or extensive hidden paralogy for each protein domain. However, rather than using GNE as a phylogenetic character, we argue that rare genomic changes such as the one presented here should be used with caution.


Assuntos
Evolução Molecular , Transferência Genética Horizontal/genética , Invertebrados/genética , Filogenia , Animais , Carboidratos Epimerases/biossíntese , Carboidratos Epimerases/genética , Funções Verossimilhança , Modelos Genéticos
17.
Mol Biol Evol ; 28(3): 1241-1254, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21087945

RESUMO

How animals (metazoans) originated from their single-celled ancestors remains a major question in biology. As transcriptional regulation is crucial to animal development, deciphering the early evolution of associated transcription factors (TFs) is critical to understanding metazoan origins. In this study, we uncovered the repertoire of 17 metazoan TFs in the amoeboid holozoan Capsaspora owczarzaki, a representative of a unicellular lineage that is closely related to choanoflagellates and metazoans. Phylogenetic and comparative genomic analyses with the broadest possible taxonomic sampling allowed us to formulate new hypotheses regarding the origin and evolution of developmental metazoan TFs. We show that the complexity of the TF repertoire in C. owczarzaki is strikingly high, pushing back further the origin of some TFs formerly thought to be metazoan specific, such as T-box or Runx. Nonetheless, TF families whose beginnings antedate the origin of the animal kingdom, such as homeodomain or basic helix-loop-helix, underwent significant expansion and diversification along metazoan and eumetazoan stems.


Assuntos
Coanoflagelados/genética , Proteínas de Ligação a DNA/genética , Evolução Molecular , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Coanoflagelados/classificação , Proteínas de Ligação a DNA/classificação , Genômica , Dados de Sequência Molecular , Filogenia , Fatores de Transcrição/classificação
18.
Genome Biol ; 23(1): 163, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35883107

RESUMO

BACKGROUND: Cytosine DNA methylation is widely described as a transcriptional repressive mark with the capacity to silence promoters. Epigenome engineering techniques enable direct testing of the effect of induced DNA methylation on endogenous promoters; however, the downstream effects have not yet been comprehensively assessed. RESULTS: Here, we simultaneously induce methylation at thousands of promoters in human cells using an engineered zinc finger-DNMT3A fusion protein, enabling us to test the effect of forced DNA methylation upon transcription, chromatin accessibility, histone modifications, and DNA methylation persistence after the removal of the fusion protein. We find that transcriptional responses to DNA methylation are highly context-specific, including lack of repression, as well as cases of increased gene expression, which appears to be driven by the eviction of methyl-sensitive transcriptional repressors. Furthermore, we find that some regulatory networks can override DNA methylation and that promoter methylation can cause alternative promoter usage. DNA methylation deposited at promoter and distal regulatory regions is rapidly erased after removal of the zinc finger-DNMT3A fusion protein, in a process combining passive and TET-mediated demethylation. Finally, we demonstrate that induced DNA methylation can exist simultaneously on promoter nucleosomes that possess the active histone modification H3K4me3, or DNA bound by the initiated form of RNA polymerase II. CONCLUSIONS: These findings have important implications for epigenome engineering and demonstrate that the response of promoters to DNA methylation is more complex than previously appreciated.


Assuntos
DNA (Citosina-5-)-Metiltransferases , Metilação de DNA , Cromatina , Ilhas de CpG , DNA/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Humanos , Regiões Promotoras Genéticas , Fatores de Transcrição/metabolismo
19.
Nat Ecol Evol ; 5(3): 369-378, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33462491

RESUMO

Mammalian brains feature exceptionally high levels of non-CpG DNA methylation alongside the canonical form of CpG methylation. Non-CpG methylation plays a critical regulatory role in cognitive function, which is mediated by the binding of MeCP2, the transcriptional regulator that when mutated causes Rett syndrome. However, it is unclear whether the non-CpG neural methylation system is restricted to mammalian species with complex cognitive abilities or has deeper evolutionary origins. To test this, we investigated brain DNA methylation across 12 distantly related animal lineages, revealing that non-CpG methylation is restricted to vertebrates. We discovered that in vertebrates, non-CpG methylation is enriched within a highly conserved set of developmental genes transcriptionally repressed in adult brains, indicating that it demarcates a deeply conserved regulatory program. We also found that the writer of non-CpG methylation, DNMT3A, and the reader, MeCP2, originated at the onset of vertebrates as a result of the ancestral vertebrate whole-genome duplication. Together, we demonstrate how this novel layer of epigenetic information assembled at the root of vertebrates and gained new regulatory roles independent of the ancestral form of the canonical CpG methylation. This suggests that the emergence of non-CpG methylation may have fostered the evolution of sophisticated cognitive abilities found in the vertebrate lineage.


Assuntos
Metilação de DNA , Proteína 2 de Ligação a Metil-CpG , Animais , Encéfalo/metabolismo , Genoma , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Vertebrados/genética
20.
BMC Evol Biol ; 10: 93, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20359327

RESUMO

BACKGROUND: Cell-to-cell communication is a key process in multicellular organisms. In multicellular animals, scaffolding proteins belonging to the family of membrane-associated guanylate kinases (MAGUK) are involved in the regulation and formation of cell junctions. These MAGUK proteins were believed to be exclusive to Metazoa. However, a MAGUK gene was recently identified in an EST survey of Capsaspora owczarzaki, an unicellular organism that branches off near the metazoan clade. To further investigate the evolutionary history of MAGUK, we have undertook a broader search for this gene family using available genomic sequences of different opisthokont taxa. RESULTS: Our survey and phylogenetic analyses show that MAGUK proteins are present not only in Metazoa, but also in the choanoflagellate Monosiga brevicollis and in the protist Capsaspora owczarzaki. However, MAGUKs are absent from fungi, amoebozoans or any other eukaryote. The repertoire of MAGUKs in Placozoa and eumetazoan taxa (Cnidaria + Bilateria) is quite similar, except for one class that is missing in Trichoplax, while Porifera have a simpler MAGUK repertoire. However, Vertebrata have undergone several independent duplications and exhibit two exclusive MAGUK classes. Three different MAGUK types are found in both M. brevicollis and C. owczarzaki: DLG, MPP and MAGI. Furthermore, M. brevicollis has suffered a lineage-specific diversification. CONCLUSIONS: The diversification of the MAGUK protein gene family occurred, most probably, prior to the divergence between Metazoa+choanoflagellates and the Capsaspora+Ministeria clade. A MAGI-like, a DLG-like, and a MPP-like ancestral genes were already present in the unicellular ancestor of Metazoa, and new gene members have been incorporated through metazoan evolution within two major periods, one before the sponge-eumetazoan split and another within the vertebrate lineage. Moreover, choanoflagellates have suffered an independent MAGUK diversification. This study highlights the importance of generating enough genome data from the broadest possible taxonomic sampling, in order to fully understand the evolutionary history of major protein gene families.


Assuntos
Eucariotos/genética , Evolução Molecular , Guanilato Quinases/genética , Animais , Guanilato Quinases/química , Filogenia
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