scholarly journals Topological isolation of developmental regulators in mammalian genomes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hua-Jun Wu ◽  
Alexandro Landshammer ◽  
Elena K. Stamenova ◽  
Adriano Bolondi ◽  
Helene Kretzmer ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Purifying Selection ◽  
Gene Isolation ◽  
Regulatory Control ◽  
Developmental Gene ◽  
Distal Enhancer ◽  
Precise Control ◽  
Mammalian Genomes ◽  
Loop Domains ◽  
Mammalian Gene Expression

AbstractPrecise control of mammalian gene expression is facilitated through epigenetic mechanisms and nuclear organization. In particular, insulated chromosome structures are important for regulatory control, but the phenotypic consequences of their boundary disruption on developmental processes are complex and remain insufficiently understood. Here, we generated deeply sequenced Hi-C data for human pluripotent stem cells (hPSCs) that allowed us to identify CTCF loop domains that have highly conserved boundary CTCF sites and show a notable enrichment of individual developmental regulators. Importantly, perturbation of such a boundary in hPSCs interfered with proper differentiation through deregulated distal enhancer-promoter activity. Finally, we found that germline variations affecting such boundaries are subject to purifying selection and are underrepresented in the human population. Taken together, our findings highlight the importance of developmental gene isolation through chromosomal folding structures as a mechanism to ensure their proper expression.

scholarly journals Quantitative translation of dog-to-human aging by conserved remodeling of epigenetic networks

2019 ◽  
Author(s):  
Tina Wang ◽  
Jianzhu Ma ◽  
Andrew N. Hogan ◽  
Samson Fong ◽  
Katherine Licon ◽  
...  
Keyword(s):  
Gene Networks ◽  
Nonlinear Relationship ◽  
Epigenetic Changes ◽  
Developmental Gene ◽  
Molecular Events ◽  
Mammalian Genomes ◽  
Age Range ◽  
Labrador Retrievers ◽  
Evolutionary Comparisons ◽  
Diagnostic Age

SUMMARYMammals progress through similar physiological stages during life, from early development to puberty, aging, and death. Yet, the extent to which this conserved physiology reflects conserved molecular events is unclear. Here, we map common epigenetic changes experienced by mammalian genomes as they age, focusing on evolutionary comparisons of humans to dogs, an emerging model of aging. Using targeted sequencing, we characterize the methylomes of 104 Labrador retrievers spanning a 16 year age range, achieving >150X coverage within mammalian syntenic blocks. Comparison with human methylomes reveals a nonlinear relationship which translates dog to human years, aligns the timing of major physiological milestones between the two species, and extends to mice. Conserved changes center on specific developmental gene networks which are sufficient to capture the effects of anti-aging interventions in multiple mammals. These results establish methylation not only as a diagnostic age readout but as a cross-species translator of physiological aging milestones.

scholarly journals Computational prediction of CTCF/cohesin-based intra-TAD loops that insulate chromatin contacts and gene expression in mouse liver

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Bryan J Matthews ◽  
David J Waxman
Keyword(s):  
Nuclear Organization ◽  
Computational Prediction ◽  
Computational Method ◽  
Regulatory Control ◽  
Ctcf Binding ◽  
Distal Enhancer ◽  
Enhancer Activity ◽  
Repressive Histone Mark ◽  
Functional Features ◽  
High Level

CTCF and cohesin are key drivers of 3D-nuclear organization, anchoring the megabase-scale Topologically Associating Domains (TADs) that segment the genome. Here, we present and validate a computational method to predict cohesin-and-CTCF binding sites that form intra-TAD DNA loops. The intra-TAD loop anchors identified are structurally indistinguishable from TAD anchors regarding binding partners, sequence conservation, and resistance to cohesin knockdown; further, the intra-TAD loops retain key functional features of TADs, including chromatin contact insulation, blockage of repressive histone mark spread, and ubiquity across tissues. We propose that intra-TAD loops form by the same loop extrusion mechanism as the larger TAD loops, and that their shorter length enables finer regulatory control in restricting enhancer-promoter interactions, which enables selective, high-level expression of gene targets of super-enhancers and genes located within repressive nuclear compartments. These findings elucidate the role of intra-TAD cohesin-and-CTCF binding in nuclear organization associated with widespread insulation of distal enhancer activity.

scholarly journals Comprehensive genomic analysis reveals dynamic evolution of endogenous retroviruses that code for retroviral-like protein domains

Mobile DNA ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mahoko Takahashi Ueda ◽  
Kirill Kryukov ◽  
Satomi Mitsuhashi ◽  
Hiroaki Mitsuhashi ◽  
Tadashi Imanishi ◽  
...  
Keyword(s):  
Host Species ◽  
Protein Domains ◽  
Genomic Analysis ◽  
Purifying Selection ◽  
Synonymous Substitution ◽  
Endogenous Retroviruses ◽  
Open Reading Frames ◽  
Consensus Sequences ◽  
Mammalian Genomes ◽  
Species Specific

Abstract Background Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections of mammalian germline cells. A large proportion of ERVs lose their open reading frames (ORFs), while others retain them and become exapted by the host species. However, it remains unclear what proportion of ERVs possess ORFs (ERV-ORFs), become transcribed, and serve as candidates for co-opted genes. Results We investigated characteristics of 176,401 ERV-ORFs containing retroviral-like protein domains (gag, pro, pol, and env) in 19 mammalian genomes. The fractions of ERVs possessing ORFs were overall small (~ 0.15%) although they varied depending on domain types as well as species. The observed divergence of ERV-ORF from their consensus sequences showed bimodal distributions, suggesting that a large proportion of ERV-ORFs either recently, or anciently, inserted themselves into mammalian genomes. Alternatively, very few ERVs lacking ORFs were found to exhibit similar divergence patterns. To identify candidates for ERV-derived genes, we estimated the ratio of non-synonymous to synonymous substitution rates (dN/dS) for ERV-ORFs in human and non-human mammalian pairs, and found that approximately 42% of the ERV-ORFs showed dN/dS < 1. Further, using functional genomics data including transcriptome sequencing, we determined that approximately 9.7% of these selected ERV-ORFs exhibited transcriptional potential. Conclusions These results suggest that purifying selection operates on a certain portion of ERV-ORFs, some of which may correspond to uncharacterized functional genes hidden within mammalian genomes. Together, our analyses suggest that more ERV-ORFs may be co-opted in a host-species specific manner than we currently know, which are likely to have contributed to mammalian evolution and diversification.

scholarly journals Mechanism of REST/NRSF regulation of clustered protocadherin α genes

2021 ◽  
Author(s):  
Yuanxiao Tang ◽  
Zhilian Jia ◽  
Honglin Xu ◽  
Lin-tai Da ◽  
Qiang Wu
Keyword(s):  
Gene Expression ◽  
Conformational Changes ◽  
Target Genes ◽  
Regulation Mechanism ◽  
Specific Interactions ◽  
Binding Pattern ◽  
Distal Enhancer ◽  
Mammalian Genomes ◽  
Silencer Elements ◽  
Repressor Element

Abstract Repressor element-1 silencing transcription factor (REST) or neuron-restrictive silencer factor (NRSF) is a zinc-finger (ZF) containing transcriptional repressor that recognizes thousands of neuron-restrictive silencer elements (NRSEs) in mammalian genomes. How REST/NRSF regulates gene expression remains incompletely understood. Here, we investigate the binding pattern and regulation mechanism of REST/NRSF in the clustered protocadherin (PCDH) genes. We find that REST/NRSF directionally forms base-specific interactions with NRSEs via tandem ZFs in an anti-parallel manner but with striking conformational changes. In addition, REST/NRSF recruitment to the HS5–1 enhancer leads to the decrease of long-range enhancer-promoter interactions and downregulation of the clustered PCDHα genes. Thus, REST/NRSF represses PCDHα gene expression through directional binding to a repertoire of NRSEs within the distal enhancer and variable target genes.

scholarly journals Molecular properties and evolutionary origins of a parvovirus-derived myosin fusion gene in guinea pigs

2019 ◽  
Author(s):  
Ignacio Valencia-Herrera ◽  
Eduardo Cena-Ahumada ◽  
Fernando Faunes ◽  
Rodrigo Ibarra-Karmy ◽  
Robert J. Gifford ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Guinea Pigs ◽  
Fusion Gene ◽  
Purifying Selection ◽  
Evolutionary Origins ◽  
Evolutionarily Conserved ◽  
Mammalian Genomes ◽  
Multiple Species ◽  
The Impact

AbstractSequences derived from parvoviruses (familyParvoviridae) are relatively common in animal genomes, but the functional significance of these endogenous parvoviral element (EPV) sequences remains unclear. In this study we use a combination ofin silicoand molecular biological approaches to investigate a fusion gene encoded by guinea pigs (genusCavia) that is partially derived from an EPV. This gene, namedenRep-Myo9, encodes a predicted polypeptide gene product comprising a partialmyosin9 (Myo9)-like gene fused to a 3’ truncated, EPV- encoded replicase. We first examined the genomic and phylogenetic characteristics of the EPV locus that encodes the viral portions ofenRep-Myo9. We show that this locus, named enRep, is specific to guinea pigs and derives from an ancient representative of the parvoviral genusDependoparvovirusthat integrated into the guinea pig germline 22-35 million years ago. Despite these ancient origins, however, the regions of enRep that are incorporated into the coding sequence of theenRep-Myo9gene are conserved across multiple species in the family Caviidae (guinea pigs and cavies) consistent with purifying selection. Using molecular biological approaches, we further demonstrate that: (i)enRep-Myo9mRNA is broadly transcribed in guinea pig cells; (ii) the clonedenRep-Myo9transcript can express a protein of the expected size in guinea pig cellsin vitro, and; (iii) the expressed protein localizes to the cytosol. Our findings demonstrate that, consistent with a functional role, theenRep-Myo9fusion gene is evolutionarily conserved, broadly transcribed, and capable of expressing protein.ImportanceDNA from viruses has been ‘horizontally transferred’ to mammalian genomes during evolution, but the impact of this process on mammalian biology remains poorly understood. The findings of our study indicate that in guinea pigs a novel gene has evolved through fusion of host and virus genes.

scholarly journals Mechanism of REST/NRSF Regulation of Clustered Protocadherin α Genes

2021 ◽  
Author(s):  
Yuanxiao Tang ◽  
Zhilian Jia ◽  
Honglin Xu ◽  
Lin-Tai Da ◽  
Qiang Wu
Keyword(s):  
Gene Expression ◽  
Conformational Changes ◽  
Target Genes ◽  
Regulation Mechanism ◽  
Specific Interactions ◽  
Binding Pattern ◽  
Distal Enhancer ◽  
Mammalian Genomes ◽  
Silencer Elements ◽  
Repressor Element

ABSTRACTRepressor element-1 silencing transcription factor (REST) or neuron-restrictive silencer factor (NRSF) is a zinc-finger (ZF) containing transcriptional repressor that recognizes thousands of neuron-restrictive silencer elements (NRSEs) in mammalian genomes. How REST/NRSF regulates gene expression remains incompletely understood. Here, we investigate the binding pattern and regulation mechanism of REST/NRSF in the clustered protocadherin (PCDH) genes. We find that REST/NRSF directionally forms base-specific interactions with NRSEs via tandem ZFs in an anti-parallel manner but with striking conformational changes. In addition, REST/NRSF recruitment to the HS5-1 enhancer leads to the decrease of long-range enhancer-promoter interactions and downregulation of the clustered PCDHα genes. Thus, REST/NRSF represses PCDHα gene expression through directional binding to a repertoire of NRSEs within the distal enhancer and variable target genes.

scholarly journals Insulation of gene expression by CTCF and cohesin-based subTAD (ubiquitous intra-TAD) loop structures in mouse liver

2018 ◽  
Author(s):  
Bryan J. Matthews ◽  
David J. Waxman
Keyword(s):  
Gene Expression ◽  
Nuclear Organization ◽  
Computational Method ◽  
Regulatory Control ◽  
Ctcf Binding ◽  
Distal Enhancer ◽  
Repressive Histone Mark ◽  
Extrusion Mechanism ◽  
Functional Features

ABSTRACTCTCF and cohesin are key drivers of 3D-nuclear organization, anchoring the megabase-scale Topologically Associating Domains (TADs) that segment the genome. Here, we present a computational method to identify cohesin-and-CTCF binding sites that form intra-TAD DNA loops (subTADs). We show that predicted subTAD anchors are structurally indistinguishable from those of TADs regarding their binding partners, sequence conservation, and resistance to cohesin knockdown; further, the subTAD loops retain key functional features of TADs, including insulation of chromatin contacts, blockage of repressive histone mark spread, and ubiquity across tissues. We propose that subTADs form by the same loop extrusion mechanism as larger loops, and that their shorter length enables finer regulatory control over gene expression. 4C-seq analysis using an Alb promoter viewpoint illustrates the role of subTADs in restricting enhancer-promoter interactions. These findings elucidate the role of intra-TAD cohesin-and-CTCF binding in nuclear organization, and demonstrate that distal enhancer insulation by subTADs is widespread.

scholarly journals Transposable Element-Gene Splicing Modulates the Transcriptional Landscape of Human Pluripotent Stem Cells

2020 ◽  
Author(s):  
Isaac A. Babarinde ◽  
Gang Ma ◽  
Yuhao Li ◽  
Boping Deng ◽  
Zhiwei Luo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Genome Stability ◽  
Human Pluripotent Stem Cells ◽  
Endogenous Retroviruses ◽  
Rna Seq ◽  
Protein Coding ◽  
Gene Splicing ◽  
Mammalian Genomes ◽  
And Function

AbstractTransposable elements (TEs) occupy nearly 50% of mammalian genomes and are both potential dangers to genome stability and functional genetic elements. TEs can be expressed and exonised as part of a transcript, however, their full contribution to the transcript splicing remains unresolved. Here, guided by long and short read sequencing of RNAs, we show that 26% of coding and 65% of non-coding transcripts of human pluripotent stem cells (hPSCs) contain TEs. Different TE families have unique integration patterns with diverse consequences on RNA expression and function. We identify hPSC-specific splicing of endogenous retroviruses (ERVs) as well as LINE L1 elements into protein coding genes that generate TE-derived peptides. Finally, single cell RNA-seq reveals that proliferating hPSCs are dominated by ERV-containing transcripts, and subpopulations express SINE or LINE-containing transcripts. Overall, we demonstrate that TE splicing modulates the pluripotency transcriptome by enhancing and impairing transcript expression and generating novel transcripts and peptides.

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