scholarly journals Analysis of gene network bifurcation during optic cup morphogenesis in zebrafish

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lorena Buono ◽  
Jorge Corbacho ◽  
Silvia Naranjo ◽  
María Almuedo-Castillo ◽  
Tania Moreno-Marmol ◽  
...  
Keyword(s):  
Single Gene ◽  
Chromatin Accessibility ◽  
Genetic Studies ◽  
Regulatory Modules ◽  
Eye Disorders ◽  
Dependent Activity ◽  
Pigmented Epithelium ◽  
Gene Regulatory ◽  
Early Recruitment ◽  
Upstream Regulators

AbstractSight depends on the tight cooperation between photoreceptors and pigmented cells, which derive from common progenitors through the bifurcation of a single gene regulatory network into the neural retina (NR) and retinal-pigmented epithelium (RPE) programs. Although genetic studies have identified upstream nodes controlling these networks, their regulatory logic remains poorly investigated. Here, we characterize transcriptome dynamics and chromatin accessibility in segregating NR/RPE populations in zebrafish. We analyze cis-regulatory modules and enriched transcription factor motives to show extensive network redundancy and context-dependent activity. We identify downstream targets, highlighting an early recruitment of desmosomal genes in the flattening RPE and revealing Tead factors as upstream regulators. We investigate the RPE specification network dynamics to uncover an unexpected sequence of transcription factors recruitment, which is conserved in humans. This systematic interrogation of the NR/RPE bifurcation should improve both genetic counseling for eye disorders and hiPSCs-to-RPE differentiation protocols for cell-replacement therapies in degenerative diseases.

scholarly journals Analysis of gene network bifurcation during optic cup morphogenesis in zebrafish

2020 ◽  
Author(s):  
Lorena Buono ◽  
Silvia Naranjo ◽  
Tania Moreno-Marmol ◽  
Berta de la Cerda ◽  
Rocío Polvillo ◽  
...  
Keyword(s):  
Single Gene ◽  
Chromatin Accessibility ◽  
Rna Seq ◽  
Genetic Studies ◽  
Regulatory Modules ◽  
Eye Disorders ◽  
Pigmented Epithelium ◽  
Gene Regulatory ◽  
Early Recruitment ◽  
Upstream Regulators

SummarySight depends on the tight cooperation between photoreceptors and pigmented cells. Both derive from common progenitors in which a single gene regulatory network (GRN) bifurcates into the neural retina (NR) and retinal-pigmented epithelium (RPE) programs. Although genetic studies have identified upstream nodes controlling these networks, their regulatory logic remains poorly investigated. Here, we characterize transcriptome dynamics (RNA-seq) and chromatin accessibility (ATAC-seq) in segregating NR/RPE populations in zebrafish. Analysis of active cis-regulatory modules and enriched transcription factor (TF) motives suggest extensive network redundancy and context-dependent TF activity. Downstream targets identification highlights an early recruitment of desmosomal genes in the flattening RPE, revealing Tead factors as upstream regulators. Investigation of GRNs dynamics uncovers an unexpected sequence of TF recruitment during RPE specification, which is conserved in humans. This systematic interrogation of the NR/RPE bifurcation should improve both genetic counselling for eye disorders and hiPSCs-to-RPE differentiation protocols for cell-replacement therapies in degenerative diseases.

scholarly journals Evolution and multiple roles of the Pancrustacea specific transcription factor zelda in insects

2017 ◽  
Author(s):  
Lupis Ribeiro ◽  
Vitória Tobias-Santos ◽  
Danielle Santos ◽  
Felipe Antunes ◽  
Geórgia Feltran ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Chromatin Accessibility ◽  
Multiple Roles ◽  
Biological Processes ◽  
Regulatory Modules ◽  
Ancestral Function ◽  
Gene Regulatory ◽  
Whole Egg

SummaryGene regulatory networks (GRN) evolve as a result of the coevolutionary process acting on transcription factors and the cis-regulatory modules (CRMs) they bind. The zinc-finger transcription factor (TF) zelda (zld) is essential for maternal zygotic transition (MZT) in Drosophila melanogaster, where it directly binds over thousand CRMs to regulate chromatin accessibility. D. melanogaster displays a long germ type of embryonic development, where all segments are simultaneously generated along the whole egg. However, it remains unclear if zld is also involved in MZT of short-germ insects (including those from basal lineages) or in other biological processes. Here we show that zld is an innovation of the Pancrustacea lineage, being absent in more distant arthropods (e.g. chelicerates) and other organisms. To better understand zld’s ancestral function, we thoroughly investigated its roles in a short-germ beetle, Tribolium castaneum, using molecular biology and computational approaches. Our results demonstrate roles for zld not only during the MZT, but also in posterior segmentation and patterning of imaginal disc derived structures. Further, we also demonstrate that zld is critical for posterior segmentation in the hemipteran Rhodnius prolixus, indicating this function predates the origin of holometabolous insects and was subsequently lost in long-germ insects. Our results unveil new roles of zld in maintaining pluripotent state of progenitor cells at the posterior region and suggest that changes in expression of zld (and probably other pioneer TFs) are critical in the evolution of insect GRNs.

scholarly journals Shared associations identify causal relationships between gene expression and immune cell phenotypes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Christiane Gasperi ◽  
Sung Chun ◽  
Shamil R. Sunyaev ◽  
Chris Cotsapas
Keyword(s):  
Complex Traits ◽  
Direct Evidence ◽  
Immune Cell ◽  
Genetic Locus ◽  
Causal Variant ◽  
Causal Relationships ◽  
Genetic Studies ◽  
Two Factors ◽  
Gene Regulatory ◽  
Cell Phenotypes

AbstractGenetic mapping studies have identified thousands of associations between common variants and hundreds of human traits. Translating these associations into mechanisms is complicated by two factors: they fall into gene regulatory regions; and they are rarely mapped to one causal variant. One way around these limitations is to find groups of traits that share associations, using this genetic link to infer a biological connection. Here, we assess how many trait associations in the same locus are due to the same genetic variant, and thus shared; and if these shared associations are due to causal relationships between traits. We find that only a subset of traits share associations, with many due to causal relationships rather than pleiotropy. We therefore suggest that simply observing overlapping associations at a genetic locus is insufficient to infer causality; direct evidence of shared associations is required to support mechanistic hypotheses in genetic studies of complex traits.

scholarly journals Chromatin dynamics during hematopoiesis reveal discrete regulatory modules instructing differentiation

2020 ◽  
Author(s):  
Grigorios Georgolopoulos ◽  
Mineo Iwata ◽  
Nikoletta Psatha ◽  
Andrew Nishida ◽  
Tannishtha Som ◽  
...  
Keyword(s):  
Temporal Dynamics ◽  
Ex Vivo ◽  
Chromatin Accessibility ◽  
Dnase I ◽  
Lineage Commitment ◽  
Gene Promoters ◽  
Chromatin Dynamics ◽  
Regulatory Modules ◽  
Hypersensitive Sites ◽  
Regulatory Landscape

AbstractLineage commitment and differentiation is driven by the concerted action of master transcriptional regulators at their target chromatin sites. Multiple efforts have characterized the key transcription factors (TFs) that determine the various hematopoietic lineages. However, the temporal interactions between individual TFs and their chromatin targets during differentiation and how these interactions dictate lineage commitment remains poorly understood. We performed dense, daily, temporal profiling of chromatin accessibility (DNase I-seq) and gene expression changes (total RNA-seq) along ex vivo human erythropoiesis to comprehensively define developmentally regulated DNase I hypersensitive sites (DHSs) and transcripts. We link both distal DHSs to their target gene promoters and individual TFs to their target DHSs, revealing that the regulatory landscape is organized in distinct sequential regulatory modules that regulate lineage restriction and maturation. Finally, direct comparison of transcriptional dynamics (bulk and single-cell) and lineage potential between erythropoiesis and megakaryopoiesis illuminates the fine-scale temporal dynamics of these regulatory modules during lineage-resolution between these two fates. Collectively, these data provide novel insights into the global regulatory landscape during hematopoiesis.

scholarly journals Active enhancer and chromatin accessibility landscapes chart the regulatory network of primary multiple myeloma

Blood ◽  
2018 ◽  
Vol 131 (19) ◽  
pp. 2138-2150 ◽  
Author(s):  
Yi Jin ◽  
Kenian Chen ◽  
Ayla De Paepe ◽  
Eva Hellqvist ◽  
Aleksandra D. Krstic ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Regulatory Network ◽  
Chromatin Accessibility ◽  
Epigenetic Changes ◽  
Active Enhancer ◽  
Key Points ◽  
Gene Regulatory

Key Points Gene regulatory features in MM patients reveal a key regulatory network and epigenetic changes that underpin the disease.

scholarly journals The bowfin genome illuminates the developmental evolution of ray-finned fishes

2021 ◽  
Vol 53 (9) ◽  
pp. 1373-1384 ◽  
Author(s):  
Andrew W. Thompson ◽  
M. Brent Hawkins ◽  
Elise Parey ◽  
Dustin J. Wcisel ◽  
Tatsuya Ota ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Order ◽  
Chromatin Accessibility ◽  
Phylogenetic Position ◽  
Developmental Evolution ◽  
Bony Fishes ◽  
Regulatory Loci ◽  
Gene Regulatory ◽  
Amia Calva ◽  
Chromosome Level

AbstractThe bowfin (Amia calva) is a ray-finned fish that possesses a unique suite of ancestral and derived phenotypes, which are key to understanding vertebrate evolution. The phylogenetic position of bowfin as a representative of neopterygian fishes, its archetypical body plan and its unduplicated and slowly evolving genome make bowfin a central species for the genomic exploration of ray-finned fishes. Here we present a chromosome-level genome assembly for bowfin that enables gene-order analyses, settling long-debated neopterygian phylogenetic relationships. We examine chromatin accessibility and gene expression through bowfin development to investigate the evolution of immune, scale, respiratory and fin skeletal systems and identify hundreds of gene-regulatory loci conserved across vertebrates. These resources connect developmental evolution among bony fishes, further highlighting the bowfin’s importance for illuminating vertebrate biology and diversity in the genomic era.

scholarly journals Drug-induced chromatin accessibility changes associate with sensitivity to liver tumor promotion

2019 ◽  
Vol 2 (5) ◽  
pp. e201900461 ◽  
Author(s):  
Antonio Vitobello ◽  
Juliane Perner ◽  
Johanna Beil ◽  
Jiang Zhu ◽  
Alberto Del Río-Espínola ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Liver Tumor ◽  
Tumor Promotion ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Cancer Risk Assessment ◽  
Resistant Mouse ◽  
Early Stages ◽  
Gene Regulatory Elements ◽  
Gene Regulatory

Liver cancer susceptibility varies amongst humans and between experimental animal models because of multiple genetic and epigenetic factors. The molecular characterization of such susceptibilities has the potential to enhance cancer risk assessment of xenobiotic exposures and disease prevention strategies. Here, using DNase I hypersensitivity mapping coupled with transcriptomic profiling, we investigate perturbations in cis-acting gene regulatory elements associated with the early stages of phenobarbital (PB)-mediated liver tumor promotion in susceptible versus resistant mouse strains (B6C3F1 versus C57BL/6J). Integrated computational analyses of strain-selective changes in liver chromatin accessibility underlying PB response reveal differential epigenetic regulation of molecular pathways associated with PB-mediated tumor promotion, including Wnt/β-catenin signaling. Complementary transcription factor motif analyses reveal mouse strain–selective gene regulatory networks and a novel role for Stat, Smad, and Fox transcription factors in the early stages of PB-mediated tumor promotion. Mapping perturbations in cis-acting gene regulatory elements provides novel insights into the molecular basis for susceptibility to xenobiotic-induced rodent liver tumor promotion and has the potential to enhance mechanism-based cancer risk assessments of xenobiotic exposures.

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