Publications
191 results found
Paterson HAB, Yu S, Artigas N, et al., 2022, Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice, Nature Metabolism, Vol: 4, Pages: 1812-1829, ISSN: 2522-5812
RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein 2 (RBFOX2) in maintaining cholesterol homeostasis in a lipogenic environment in the liver. Using enhanced individual-nucleotide-resolution ultra-violet cross-linking and immunoprecipitation, we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesity-induced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases.
Guo Y, Al-Jibury E, Garcia-Millan R, et al., 2022, Chromatin jets define the properties of cohesin-driven in vivo loop extrusion, Molecular Cell, Vol: 82, Pages: 3769-3780.e5, ISSN: 1097-2765
Complex genomes show intricate organization in three-dimensional (3D) nuclear space. Current models posit that cohesin extrudes loops to form self-interacting domains delimited by the DNA binding protein CTCF. Here, we describe and quantitatively characterize cohesin-propelled, jet-like chromatin contacts as landmarks of loop extrusion in quiescent mammalian lymphocytes. Experimental observations and polymer simulations indicate that narrow origins of loop extrusion favor jet formation. Unless constrained by CTCF, jets propagate symmetrically for 1-2 Mb, providing an estimate for the range of in vivo loop extrusion. Asymmetric CTCF binding deflects the angle of jet propagation as experimental evidence that cohesin-mediated loop extrusion can switch from bi- to unidirectional and is controlled independently in both directions. These data offer new insights into the physiological behavior of in vivo cohesin-mediated loop extrusion and further our understanding of the principles that underlie genome organization.
Baranasic D, Hortenhuber M, Balwierz PJ, et al., 2022, Multiomic atlas with functional stratification and developmental dynamics of zebrafish cis-regulatory elements, NATURE GENETICS, Vol: 54, Pages: 1037-+, ISSN: 1061-4036
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- Citations: 3
Jobbins AM, Haberman N, Artigas N, et al., 2022, Dysregulated RNA polyadenylation contributes to metabolic impairment in non-alcoholic fatty liver disease, Nucleic Acids Research, Vol: 50, Pages: 3379-3393, ISSN: 0305-1048
Pre-mRNA processing is an essential mechanism for the generation of mature mRNA and the regulation of gene expression in eukaryotic cells. While defects in pre-mRNA processing have been implicated in a number of diseases their involvement in metabolic pathologies is still unclear. Here, we show that both alternative splicing and alternative polyadenylation, two major steps in pre-mRNA processing, are significantly altered in non-alcoholic fatty liver disease (NAFLD). Moreover, we find that Serine and Arginine Rich Splicing Factor 10 (SRSF10) binding is enriched adjacent to consensus polyadenylation motifs and its expression is significantly decreased in NAFLD, suggesting a role mediating pre-mRNA dysregulation in this condition. Consistently, inactivation of SRSF10 in mouse and human hepatocytes in vitro, and in mouse liver in vivo, was found to dysregulate polyadenylation of key metabolic genes such as peroxisome proliferator-activated receptor alpha (PPARA) and exacerbate diet-induced metabolic dysfunction. Collectively our work implicates dysregulated pre-mRNA polyadenylation in obesity-induced liver disease and uncovers a novel role for SRSF10 in this process.
McAllan L, Baranasic D, Villicaña S, et al., 2021, Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes
<jats:title>ABSTRACT</jats:title><jats:p>DNA methylation variations are prevalent in human obesity, but evidence of a causative role in disease pathogenesis is limited. In this study, we combine epigenome-wide association and integrative genomics to investigate the impact of subcutaneous and visceral adipocyte DNA methylation variations in extreme human obesity. We identify extensive DNA methylation changes that are robustly associated with extreme obesity in combined discovery and replication analyses (N=190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P<1×10-7). Using functional interaction maps and methylation-expression association testing in human adipocytes, we connect extreme obesity-associated methylation variations to transcriptomic changes at >500 target genes. We find that disease-associated methylation variations localise to active genomic regions and transcription factor binding sites, at which DNA methylation influences transcription factor-target gene co-expression relationships. In Mendelian Randomisation analyses, we infer causal effects of DNA methylation on human obesity and obesity-induced metabolic disturbances, under genetic control, at 28 independent loci. Silencing of two target genes of causal DNA methylation variations, the<jats:italic>PRRC2A</jats:italic>and<jats:italic>LIMD2</jats:italic>genes, further reveals novel metabolic effects in adipocytes. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal genomic and molecular mechanisms through which altered DNA methylation may impact adipocyte cellular functions.</jats:p>
Castro-Mondragon JA, Riudavets-Puig R, Rauluseviciute I, et al., 2021, JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles, NUCLEIC ACIDS RESEARCH, Vol: 50, Pages: D165-D173, ISSN: 0305-1048
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- Citations: 175
Lopez-Perez AR, Balwierz PJ, Lenhard B, et al., 2021, Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics, SCIENTIFIC REPORTS, Vol: 11, ISSN: 2045-2322
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- Citations: 1
Baranasic D, Hörtenhuber M, Balwierz P, et al., 2021, Integrated annotation and analysis of genomic features reveal new types of functional elements and large-scale epigenetic phenomena in the developing zebrafish
<jats:title>Abstract</jats:title><jats:p>Zebrafish, a popular model for embryonic development and for modelling human diseases, has so far lacked a systematic functional annotation programme akin to those in other animal models. To address this, we formed the international DANIO-CODE consortium and created the first central repository to store and process zebrafish developmental functional genomic data. Our Data Coordination Center (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://danio-code.zfin.org">https://danio-code.zfin.org</jats:ext-link>) combines a total of 1,802 sets of unpublished and reanalysed published genomics data, which we used to improve existing annotations and show its utility in experimental design. We identified over 140,000 cis-regulatory elements in development, including novel classes with distinct features dependent on their activity in time and space. We delineated the distinction between regulatory elements active during zygotic genome activation and those active during organogenesis, identifying new aspects of how they relate to each other. Finally, we matched regulatory elements and epigenomic landscapes between zebrafish and mouse and predict functional relationships between them beyond sequence similarity, extending the utility of zebrafish developmental genomics to mammals.</jats:p>
López-Pérez AR, Balwierz PJ, Lenhard B, et al., 2021, Identification of Downstream Effectors of Retinoic Acid Specifying the Zebrafish Pancreas by Integrative Genomics.
<jats:title>Abstract</jats:title> <jats:p>Retinoic acid (RA) is a key signal for the specification of the pancreas. Still, the gene regulatory cascade triggered by RA in the endoderm remains poorly characterized. In this study, we investigated this regulatory network in zebrafish by combining RNA-seq, RAR ChIP-seq and ATAC-seq assays. By analysing the effect of RA and of the RA receptor (RAR) antagonist BMS439 on the transcriptome and on the chromatin accessibility of endodermal cells, we identified a large set of genes and regulatory regions regulated by RA signalling. RAR ChIP-seq further defined the direct RAR target genes in zebrafish, including <jats:italic>hox</jats:italic> genes as well as several pancreatic regulators like <jats:italic>mnx1</jats:italic>, <jats:italic>insm1b</jats:italic>, <jats:italic>hnf1ba</jats:italic> and <jats:italic>gata6</jats:italic>. Comparison of zebrafish and murine RAR ChIP-seq data highlighted the conserved direct target genes and revealed that some RAR sites are under strong evolutionary constraints. Among them, a novel highly conserved RAR-induced enhancer was identified downstream of the <jats:italic>HoxB</jats:italic> locus and driving expression in the nervous system and in the gut in a RA-dependant manner. Finally, ATAC-seq data unveiled the role of the RAR-direct targets Hnf1ba and Gata6 in opening chromatin at many regulatory loci upon RA treatment.</jats:p>
Casadio R, Lenhard B, Sternberg MJE, 2021, Computational Resources for Molecular Biology 2021, JOURNAL OF MOLECULAR BIOLOGY, Vol: 433, ISSN: 0022-2836
Bonetti A, Agostini F, Suzuki AM, et al., 2021, RADICL-seq identifies general and cell type-specific principles of genome-wide RNA-chromatin interactions (vol 11, 1018, 2020), NATURE COMMUNICATIONS, Vol: 12, ISSN: 2041-1723
Weiss FD, Calderon L, Wang Y-F, et al., 2021, Neuronal genes deregulated in Cornelia de Lange Syndrome respond to removal and reexpression of cohesin, Nature Communications, Vol: 12, ISSN: 2041-1723
Cornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterize the transcriptional profile of cortical neurons from CdLS patients and find deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupts 3D genome organization and transcriptional control in post-mitotic cortical mouse neurons, demonstrating that cohesin is continuously required for neuronal gene expression. The genes affected by acute depletion of cohesin belong to similar gene ontology classes and show significant numerical overlap with genes deregulated in CdLS. Interestingly, reconstitution of cohesin function largely rescues altered gene expression, including the expression of genes deregulated in CdLS.
D'Orazio FM, Balwierz PJ, Gonzalez AJ, et al., 2021, Germ cell differentiation requires Tdrd7-dependent chromatin and transcriptome reprogramming marked by germ plasm relocalization, DEVELOPMENTAL CELL, Vol: 56, Pages: 641-+, ISSN: 1534-5807
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- Citations: 8
Beltran T, Pahita E, Ghosh S, et al., 2021, Integrator is recruited to promoter-proximally paused RNA Pol II to generate Caenorhabditis elegans piRNA precursors, The EMBO Journal, Vol: 40, Pages: 1-17, ISSN: 0261-4189
Piwi‐interacting RNAs (piRNAs) play key roles in germline development and genome defence in metazoans. In C. elegans, piRNAs are transcribed from > 15,000 discrete genomic loci by RNA polymerase II (Pol II), resulting in 28 nt short‐capped piRNA precursors. Here, we investigate transcription termination at piRNA loci. We show that the Integrator complex, which terminates snRNA transcription, is recruited to piRNA loci. Moreover, we demonstrate that the catalytic activity of Integrator cleaves nascent capped piRNA precursors associated with promoter‐proximal Pol II, resulting in termination of transcription. Loss of Integrator activity, however, does not result in transcriptional readthrough at the majority of piRNA loci. Taken together, our results draw new parallels between snRNA and piRNA biogenesis in nematodes and provide evidence of a role for the Integrator complex as a terminator of promoter‐proximal RNA polymerase II during piRNA biogenesis.
Zeisig BB, Fung TK, Zarowiecki M, et al., 2021, Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia, SCIENCE TRANSLATIONAL MEDICINE, Vol: 13, ISSN: 1946-6234
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- Citations: 6
Karimi MM, Guo Y, Cui X, et al., 2021, The order and logic of CD4 CD8 lineage choice and differentiation in mouse thymus, Nature Communications, Vol: 12, ISSN: 2041-1723
CD4 and CD8 mark helper and cytotoxic T cell lineages, respectively, and serve as coreceptors for MHC-restricted TCR recognition. How coreceptor expression is matched with TCR specificity is central to understanding CD4/CD8 lineage choice, but visualising coreceptor gene activity in individual selection intermediates has been technically challenging. It therefore remains unclear whether the sequence of coreceptor gene expression in selection intermediates follows a stereotypic pattern, or is responsive to signaling. Here we use single cell RNA sequencing (scRNA-seq) to classify mouse thymocyte selection intermediates by coreceptor gene expression. In the unperturbed thymus, Cd4+Cd8a- selection intermediates appear before Cd4-Cd8a+ selection intermediates, but the timing of these subsets is flexible according to the strength of TCR signals. Our data show that selection intermediates discriminate MHC class prior to the loss of coreceptor expression and suggest a model where signal strength informs the timing of coreceptor gene activity and ultimately CD4/CD8 lineage choice.
Yu C, Cvetesic N, Hisler V, et al., 2020, TBPL2/TFIIA complex establishes the maternal transcriptome through oocyte-specific promoter usage, Nature Communications, Vol: 11, ISSN: 2041-1723
During oocyte growth, transcription is required to create RNA and protein reserves to achieve maternal competence. During this period, the general transcription factor TATA binding protein (TBP) is replaced by its paralogue, TBPL2 (TBP2 or TRF3), which is essential for RNA polymerase II transcription. We show that in oocytes TBPL2 does not assemble into a canonical TFIID complex. Our transcript analyses demonstrate that TBPL2 mediates transcription of oocyte-expressed genes, including mRNA survey genes, as well as specific endogenous retroviral elements. Transcription start site (TSS) mapping indicates that TBPL2 has a strong preference for TATA-like motif in core promoters driving sharp TSS selection, in contrast with canonical TBP/TFIID-driven TATA-less promoters that have broader TSS architecture. Thus, we show a role for the TBPL2/TFIIA complex in the establishment of the oocyte transcriptome by using a specific TSS recognition code.
Martin-Duran JM, Vellutini BC, Marletaz F, et al., 2020, Conservative route to genome compaction in a miniature annelid (November, 10.1038/s41559-020-01327-6, 2020), Nature Ecology and Evolution, Vol: 5, Pages: 262-262, ISSN: 2397-334X
Martin-Duran JM, Vellutini BC, Marletaz F, et al., 2020, Conservative route to genome compaction in a miniature annelid, Nature Ecology and Evolution, Vol: 5, Pages: 231-242, ISSN: 2397-334X
The causes and consequences of genome reduction in animals are unclear because our understanding of this process mostly relies on lineages with often exceptionally high rates of evolution. Here, we decode the compact 73.8-megabase genome of Dimorphilus gyrociliatus, a meiobenthic segmented worm. The D. gyrociliatus genome retains traits classically associated with larger and slower-evolving genomes, such as an ordered, intact Hox cluster, a generally conserved developmental toolkit and traces of ancestral bilaterian linkage. Unlike some other animals with small genomes, the analysis of the D. gyrociliatus epigenome revealed canonical features of genome regulation, excluding the presence of operons and trans-splicing. Instead, the gene-dense D. gyrociliatus genome presents a divergent Myc pathway, a key physiological regulator of growth, proliferation and genome stability in animals. Altogether, our results uncover a conservative route to genome compaction in annelids, reminiscent of that observed in the vertebrate Takifugu rubripes.
López-Pérez AR, Balwierz PJ, Lenhard B, et al., 2020, Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics
<jats:title>Abstract</jats:title><jats:p>Retinoic acid (RA) is a key signal for the specification of the pancreas. Still, the gene regulatory cascade triggered by RA in the endoderm remains poorly characterized. In this study, we investigated this regulatory network in zebrafish by combining RNA-seq, RAR ChIP-seq and ATAC-seq assays. By analysing the effect of RA and of the RA receptor (RAR) antagonist BMS439 on the transcriptome and on the chromatin accessibility of endodermal cells, we identified a large set of genes and regulatory regions regulated by RA signalling. RAR ChIP-seq further defined the direct RAR target genes including the known<jats:italic>hox</jats:italic>genes as well as several pancreatic regulators like<jats:italic>mnx1, insm1b, hnf1ba</jats:italic>and<jats:italic>gata6</jats:italic>. Comparison of our zebrafish data with available murine RAR ChIP-seq data highlighted conserved direct target genes and revealed that some RAR sites are under strong evolutionary constraints. Among them, a novel highly conserved RAR-induced enhancer was identified downstream of the<jats:italic>HoxB</jats:italic>locus and driving expression in the nervous system and in the gut in a RA-dependant manner. Finally, ATAC-seq data unveiled the role of the RAR-direct targets Hnf1ba and Gata6 in opening chromatin at many regulatory loci upon RA treatment.</jats:p><jats:sec><jats:title>Summary statement</jats:title><jats:p>Combination of RNA-seq, ChIP-seq and ATAC-seq assays identifies genes directly and indirectly regulated by RA signalling in zebrafish endoderm. Comparison with murine data highlights RAR binding sites conserved among vertebrates.</jats:p></jats:sec>
Cvetesic N, Borkowska M, Hatanaka Y, et al., 2020, Global regulatory transitions at core promoters demarcate the mammalian germline cycle
<jats:title>Abstract</jats:title><jats:p>Core promoters integrate regulatory inputs of genes<jats:sup>1–3</jats:sup>. Global dynamics of promoter usage can reveal systemic changes in how genomic sequence is interpreted by the cell<jats:sup>4</jats:sup> Here we report the first analysis of promoter dynamics and code switching in the mammalian germ line, characterising the full cycle of transitions from embryonic stem cells through germline, oogenesis, and zygotic genome activation. Using Super Low Input Carrier-CAGE<jats:sup>5,6</jats:sup> (SLIC-CAGE) we show that mouse germline development starts with the somatic promoter code, followed by a prominent switch to the maternal code during follicular oogenesis. The sequence features underlying the shift from somatic to maternal code are conserved across vertebrates, despite large differences in promoter nucleotide compositions. In addition, we show that, prior to this major shift, the promoters of gonadal germ cells diverge from the canonical somatic transcription initiation. This divergence is distinct from the promoter code used later by developing oocytes and reveals genome-wide promoter remodelling associated with alternative nucleosome positioning during early female and male germline development. Collectively, our findings establish promoter-level regulatory transitions as a central, conserved feature of the vertebrate life cycle.</jats:p>
Wragg JW, Roos L, Vucenovic D, et al., 2020, Embryonic tissue differentiation is characterized by transitions in cell cycle dynamic-associated core promoter regulation, NUCLEIC ACIDS RESEARCH, Vol: 48, Pages: 8374-8392, ISSN: 0305-1048
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- Citations: 2
Ramilowski JA, Yip CW, Agrawal S, et al., 2020, Functional annotation of human long noncoding RNAs via molecular phenotyping (vol 30, pg 1060, 2020), Genome Research, Vol: 30, Pages: 1377-1377, ISSN: 1054-9803
Lopez-Noriega L, Callingham R, Martinez-Sánchez A, et al., 2020, The long non-coding RNA <i>Pax6os1</i>/<i>PAX6-AS1</i> modulates pancreatic β-cell identity and function
<jats:title>Abstract</jats:title><jats:p>Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of β-cell development and function. Here, we investigate roles for an antisense lncRNA expressed from the <jats:italic>Pax6 locus</jats:italic> (annotated as <jats:italic>Pax6os1</jats:italic> in mice and <jats:italic>PAX6-AS1</jats:italic> in humans) in β-cell function. <jats:italic>Pax6os1/PAX6-AS1</jats:italic> expression was increased in islets from mice fed a high fat diet and in those from patients with type 2 diabetes. Silencing or deletion of <jats:italic>Pax6os1</jats:italic>/<jats:italic>PAX6-AS1</jats:italic> in MIN6 and EndoC-βH1cells, respectively, upregulated β-cell signature genes, including <jats:italic>Insulin</jats:italic>. Moreover, shRNA-mediated silencing of <jats:italic>PAX6-AS1</jats:italic> in human islets increased insulin mRNA, enhanced glucose-stimulated insulin secretion and calcium dynamics, while overexpressing the lncRNA reduced insulin expression and secretion. Together, our results suggest that increased expression of <jats:italic>PAX6-AS1</jats:italic> at high glucose levels may contribute to β-cell dedifferentiation and failure in some forms of type 2 diabetes. Thus, targeting <jats:italic>PAX6-AS1</jats:italic> may provide a promising strategy to enhance insulin secretion and improve glucose homeostasis in this disease.</jats:p>
Ramilowski JA, Yip CW, Agrawal S, et al., 2020, Functional annotation of human long noncoding RNAs via molecular phenotyping, Genome Research, Vol: 30, Pages: 1060-1072, ISSN: 1054-9803
Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-to-date lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.
Yu C, Cvetesic N, Hisler V, et al., 2020, TBPL2/TFIIA complex establishes the maternal transcriptome by an oocyte-specific promoter usage
<jats:title>Abstract</jats:title><jats:p>During oocyte growth, transcription is required to create RNA and protein reserves to achieve maternal competence. During this period, the general transcription factor TATA binding protein (TBP) is replaced by its paralogue, TBPL2 (TBP2 or TRF3), which is essential for RNA polymerase II transcription. We show that in oocytes TBPL2 does not assemble into a canonical TFIID complex. Our transcript analyses demonstrate that TBPL2 mediates transcription of oocyte-expressed genes, including mRNA survey genes, as well as specific endogenous retroviral elements. Transcription start site (TSS) mapping indicates that TBPL2 has a strong preference for TATA-like motif in core promoters driving sharp TSS selection, in contrast with canonical TBP/TFIID-driven TATA-less promoters that have broader TSS architecture. Thus, we show a role for the TBPL2/TFIIA complex in the establishment of the oocyte transcriptome by using a specific TSS recognition code.</jats:p>
Weiss FD, Calderon L, Wang Y-F, et al., 2020, Partial rescue of neuronal genes deregulated in Cornelia de Lange Syndrome by cohesin
<jats:title>Abstract</jats:title><jats:p>Cornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterized the transcriptional profile of cortical neurons from CdLS patients and found deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupted 3-D genome organization and transcriptional control in post-mitotic cortical mouse neurons. The genes affected belonged to similar gene ontology classes and showed significant numerical overlap with those deregulated in CdLS. Interestingly, gene expression was largely rescued by subsequent reconstitution of cohesin function. These experiments show that cohesin is continuously required for neuronal gene expression and provide a tractable approach for addressing mechanisms of neuronal dysfunction in CdLS.</jats:p>
Lewis SH, Ross L, Bain SA, et al., 2020, Widespread conservation and lineage-specific diversification of genome-wide DNA methylation patterns across arthropods, PLoS Genetics, Vol: 16, Pages: 1-24, ISSN: 1553-7390
Cytosine methylation is an ancient epigenetic modification yet its function and extent within genomes is highly variable across eukaryotes. In mammals, methylation controls transposable elements and regulates the promoters of genes. In insects, DNA methylation is generally restricted to a small subset of transcribed genes, with both intergenic regions and transposable elements (TEs) depleted of methylation. The evolutionary origin and the function of these methylation patterns are poorly understood. Here we characterise the evolution of DNA methylation across the arthropod phylum. While the common ancestor of the arthropods had low levels of TE methylation and did not methylate promoters, both of these functions have evolved independently in centipedes and mealybugs. In contrast, methylation of the exons of a subset of transcribed genes is ancestral and widely conserved across the phylum, but has been lost in specific lineages. A similar set of genes is methylated in all species that retained exon-enriched methylation. We show that these genes have characteristic patterns of expression correlating to broad transcription initiation sites and well-positioned nucleosomes, providing new insights into potential mechanisms driving methylation patterns over hundreds of millions of years.
Lenhard B, Sternberg MJE, 2020, Computational Resources for Molecular Biology: Special Issue 2020, JOURNAL OF MOLECULAR BIOLOGY, Vol: 432, Pages: 3361-3363, ISSN: 0022-2836
Martín-Durán JM, Vellutini BC, Marlétaz F, et al., 2020, Conservative route to genome compaction in a miniature annelid, Publisher: Cold Spring Harbor Laboratory
<jats:title>Summary</jats:title><jats:p>The causes and consequences of genome reduction in animals are unclear, because our understanding of this process mostly relies on lineages with often exceptionally high rates of evolution. Here, we decode the compact 73.8 Mb genome of <jats:italic>Dimorphilus gyrociliatus</jats:italic>, a meiobenthic segmented worm. The <jats:italic>D. gyrociliatus</jats:italic> genome retains traits classically associated with larger and slower-evolving genomes, such as an ordered, intact Hox cluster, a generally conserved developmental toolkit, and traces of ancestral bilaterian linkage. Unlike some other animals with small genomes, the analysis of the <jats:italic>D. gyrociliatus</jats:italic> epigenome revealed canonical features of genome regulation, excluding the presence of operons and <jats:italic>trans</jats:italic>-splicing. Instead, the gene dense <jats:italic>D. gyrociliatus</jats:italic> genome presents a divergent Myc pathway, a key physiological regulator of growth, proliferation, and genome stability in animals. Altogether, our results uncover a conservative route to genome compaction in annelids, reminiscent of that observed in the vertebrate <jats:italic>Takifugu rubripes</jats:italic>.</jats:p>
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