Endogenous retrovirus rewired the gene regulatory network shared between primordial germ cells and naïve pluripotent cells in hominoids

AbstractAlthough the gene regulatory network controlling germ cell development is critical for gamete integrity, this network has been substantially diversified during mammalian evolution. Here, we show that several hundred loci of LTR5_Hs, a hominoid-specific endogenous retrovirus (ERV), function as enhancers in both human primordial germ cells (PGCs) and naïve pluripotent cells. PGCs and naïve pluripotent cells exhibit a similar transcriptome signature, and the enhancers derived from LTR5_Hs contribute to establishing such similarity. LTR5_Hs appears to be activated by transcription factors critical in both cell types (KLF4, TFAP2C, NANOG, and CBFA2T2). Comparative transcriptome analysis between humans and macaques suggested that the expression of many genes in PGCs and naïve pluripotent cells has been upregulated by LTR5_Hs insertions in the hominoid lineage. Together, this study suggests that LTR5_Hs insertions have rewired and finetuned the gene regulatory network shared between PGCs and naïve pluripotent cells during hominoid evolution.TeaserA hominoid-specific ERV has rewired the gene regulatory network shared between PGCs and naïve pluripotent cells.

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A single cell RNA sequencing resource for early sea urchin development

Development ◽

10.1242/dev.191528 ◽

2020 ◽

Vol 147 (17) ◽

pp. dev191528 ◽

Cited By ~ 3

Author(s):

Stephany Foster ◽

Nathalie Oulhen ◽

Gary Wessel

Keyword(s):

Single Cell ◽

Rna Sequencing ◽

Gene Regulatory Network ◽

Sea Urchin ◽

Germ Cells ◽

Regulatory Network ◽

Germ Line ◽

Primordial Germ Cells ◽

Single Cell Rna Sequencing ◽

Gene Regulatory

ABSTRACTIdentifying cell states during development from their mRNA profiles provides insight into their gene regulatory network. Here, we leverage the sea urchin embryo for its well-established gene regulatory network to interrogate the embryo using single cell RNA sequencing. We tested eight developmental stages in Strongylocentrotus purpuratus, from the eight-cell stage to late in gastrulation. We used these datasets to parse out 22 major cell states of the embryo, focusing on key transition stages for cell type specification of each germ layer. Subclustering of these major embryonic domains revealed over 50 cell states with distinct transcript profiles. Furthermore, we identified the transcript profile of two cell states expressing germ cell factors, one we conclude represents the primordial germ cells and the other state is transiently present during gastrulation. We hypothesize that these cells of the Veg2 tier of the early embryo represent a lineage that converts to the germ line when the primordial germ cells are deleted. This broad resource will hopefully enable the community to identify other cell states and genes of interest to expose the underpinning of developmental mechanisms.

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Insights Into the Early Gene Regulatory Network Controlling Neural Crest and Placode Fate Choices at the Neural Border

Frontiers in Physiology ◽

10.3389/fphys.2020.608812 ◽

2020 ◽

Vol 11 ◽

Author(s):

Subham Seal ◽

Anne H. Monsoro-Burq

Keyword(s):

Neural Crest ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Cell Types ◽

Model Systems ◽

Early Gene ◽

Secretory Cells ◽

Peripheral Neurons ◽

Gene Regulatory

The neural crest (NC) cells and cranial placodes are two ectoderm-derived innovations in vertebrates that led to the acquisition of a complex head structure required for a predatory lifestyle. They both originate from the neural border (NB), a portion of the ectoderm located between the neural plate (NP), and the lateral non-neural ectoderm. The NC gives rise to a vast array of tissues and cell types such as peripheral neurons and glial cells, melanocytes, secretory cells, and cranial skeletal and connective cells. Together with cells derived from the cranial placodes, which contribute to sensory organs in the head, the NC also forms the cranial sensory ganglia. Multiple in vivo studies in different model systems have uncovered the signaling pathways and genetic factors that govern the positioning, development, and differentiation of these tissues. In this literature review, we give an overview of NC and placode development, focusing on the early gene regulatory network that controls the formation of the NB during early embryonic stages, and later dictates the choice between the NC and placode progenitor fates.

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Retrotransposons spread potential cis-regulatory elements during mammary gland evolution

Nucleic Acids Research ◽

10.1093/nar/gkz1003 ◽

2019 ◽

Cited By ~ 1

Author(s):

Hidenori Nishihara

Keyword(s):

Mammary Gland ◽

Gene Regulatory Network ◽

Binding Sites ◽

Regulatory Network ◽

Regulatory Elements ◽

Estrogen Receptor Α ◽

Endogenous Retrovirus ◽

Cis Elements ◽

Binding Motifs ◽

Gene Regulatory

Abstract Acquisition of cis-elements is a major driving force for rewiring a gene regulatory network. Several kinds of transposable elements (TEs), mostly retrotransposons that propagate via a copy-and-paste mechanism, are known to possess transcription factor binding motifs and have provided source sequences for enhancers/promoters. However, it remains largely unknown whether retrotransposons have spread the binding sites of master regulators of morphogenesis and accelerated cis-regulatory expansion involved in common mammalian morphological features during evolution. Here, I demonstrate that thousands of binding sites for estrogen receptor α (ERα) and three related pioneer factors (FoxA1, GATA3 and AP2γ) that are essential regulators of mammary gland development arose from a spreading of the binding motifs by retrotransposons. The TE-derived functional elements serve primarily as distal enhancers and are enriched around genes associated with mammary gland morphogenesis. The source TEs occurred via a two-phased expansion consisting of mainly L2/MIR in a eutherian ancestor and endogenous retrovirus 1 (ERV1) in simian primates and murines. Thus the build-up of potential sources for cis-elements by retrotransposons followed by their frequent utilization by the host (co-option/exaptation) may have a general accelerating effect on both establishing and diversifying a gene regulatory network, leading to morphological innovation.

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An Integrative Developmental Genomics and Systems Biology Approach to Identify an In Vivo Sox Trio-Mediated Gene Regulatory Network in Murine Embryos

BioMed Research International ◽

10.1155/2017/8932583 ◽

2017 ◽

Vol 2017 ◽

pp. 1-16 ◽

Cited By ~ 3

Author(s):

Wenqing Jean Lee ◽

Sumantra Chatterjee ◽

Sook Peng Yap ◽

Siew Lan Lim ◽

Xing Xing ◽

...

Keyword(s):

Systems Biology ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Regulatory Networks ◽

Cell Types ◽

Specific Cell ◽

Morpholino Knockdown ◽

Cell Type Specific ◽

Gene Regulatory

Embryogenesis is an intricate process involving multiple genes and pathways. Some of the key transcription factors controlling specific cell types are the Sox trio, namely, Sox5, Sox6, and Sox9, which play crucial roles in organogenesis working in a concerted manner. Much however still needs to be learned about their combinatorial roles during this process. A developmental genomics and systems biology approach offers to complement the reductionist methodology of current developmental biology and provide a more comprehensive and integrated view of the interrelationships of complex regulatory networks that occur during organogenesis. By combining cell type-specific transcriptome analysis and in vivo ChIP-Seq of the Sox trio using mouse embryos, we provide evidence for the direct control of Sox5 and Sox6 by the transcriptional trio in the murine model and by Morpholino knockdown in zebrafish and demonstrate the novel role of Tgfb2, Fbxl18, and Tle3 in formation of Sox5, Sox6, and Sox9 dependent tissues. Concurrently, a complete embryonic gene regulatory network has been generated, identifying a wide repertoire of genes involved and controlled by the Sox trio in the intricate process of normal embryogenesis.

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Brachyury controls Ciona notochord fate as part of a feedforward network and not as a unitary master regulator

10.1101/2020.05.29.124024 ◽

2020 ◽

Cited By ~ 2

Author(s):

Wendy M. Reeves ◽

Kotaro Shimai ◽

Konner M. Winkley ◽

Michael T. Veeman

Keyword(s):

Transcription Factor ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Cell Types ◽

Binding Motif ◽

Fgf Signaling ◽

Feedforward Network ◽

Master Regulator ◽

Gene Regulatory ◽

Direct Activator

AbstractThe notochord is a defining feature of the chordates. The transcription factor Brachyury (Bra) is a key regulator of notochord fate but here we show that it is not a unitary master regulator in the model chordate Ciona. Ectopic Bra expression only partially reprograms other cell types to a notochord-like transcriptional profile and a subset of notochord-enriched genes are unaffected by CRISPR Bra disruption. We identify Foxa.a and Mnx as potential co-regulators and find that combinatorial cocktails are more effective at reprograming other cell types than Bra alone. We reassess the network relationships between Bra, Foxa.a and other components of the notochord gene regulatory network and find that Foxa.a expression in the notochord is regulated by vegetal FGF signaling. It is a direct activator of Bra expression and has a binding motif that is significantly enriched in the regulatory regions of notochord-enriched genes. These and other results indicate that Bra and Foxa.a act together in a regulatory network dominated by positive feed-forward interactions, with neither being a classically-defined master regulator.

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Butterfly eyespots evolved via co-option of the antennal gene-regulatory network

10.1101/2021.03.01.429915 ◽

2021 ◽

Cited By ~ 1

Author(s):

Suriya Narayanan Murugesan ◽

Heidi Connahs ◽

Yuji Matsuoka ◽

Mainak das Gupta ◽

Manizah Huq ◽

...

Keyword(s):

Gene Regulatory Network ◽

Transcriptome Analysis ◽

Regulatory Network ◽

Regulatory Elements ◽

Comparative Transcriptome ◽

Comparative Transcriptome Analysis ◽

Developmental Origin ◽

Novel Traits ◽

Gene Regulatory

AbstractButterfly eyespots are beautiful novel traits with an unknown developmental origin. Here we show that eyespots likely originated via co-option of the antennal gene-regulatory network (GRN) to novel locations on the wing. Using comparative transcriptome analysis, we show that eyespots cluster with antennae relative to multiple other tissues. Furthermore, three genes essential for eyespot development (Distal-less(Dll),spalt(sal), andAntennapedia(Antp)) share similar regulatory connections as those observed in the antennal GRN. CRISPR knockout ofcis-regulatory elements (CREs) forDllandsalled to the loss of eyespots and antennae, and also legs and wings, demonstrating that these CREs are highly pleiotropic. We conclude that eyespots likely re-used the ancient antennal GRN, a network previously implicated also in the development of legs and wings.

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Brachyury controls Ciona notochord fate as part of a feedforward network

Development ◽

10.1242/dev.195230 ◽

2021 ◽

pp. dev.195230

Author(s):

Wendy M. Reeves ◽

Kotaro Shimai ◽

Konner M. Winkley ◽

Michael T. Veeman

Keyword(s):

Transcription Factor ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Cell Types ◽

Binding Motif ◽

Fgf Signaling ◽

Feedforward Network ◽

Master Regulator ◽

Gene Regulatory ◽

Direct Activator

The notochord is a defining feature of the chordates. The transcription factor Brachyury (Bra) is a key regulator of notochord fate but here we show that it is not a unitary master regulator in the model chordate Ciona. Ectopic Bra expression only partially reprograms other cell types to a notochord-like transcriptional profile and a subset of notochord-enriched genes are unaffected by CRISPR Bra disruption. We identify Foxa.a and Mnx as potential co-regulators and find that combinatorial cocktails are more effective at reprograming other cell types than Bra alone. We reassess the network relationships between Bra, Foxa.a, and other components of the notochord gene regulatory network and find that Foxa.a expression in the notochord is regulated by vegetal FGF signaling. It is a direct activator of Bra expression and has a binding motif that is significantly enriched in the regulatory regions of notochord-enriched genes. These and other results indicate that Bra and Foxa.a act together in a regulatory network dominated by positive feed-forward interactions, with neither being a classically-defined master regulator.

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Developmental gene regulatory networks in sea urchins and what we can learn from them

F1000Research ◽

10.12688/f1000research.7381.1 ◽

2016 ◽

Vol 5 ◽

pp. 203 ◽

Cited By ~ 10

Author(s):

Megan L. Martik ◽

Deirdre C. Lyons ◽

David R. McClay

Keyword(s):

Transcription Factors ◽

Gene Regulatory Network ◽

Sea Urchin ◽

Network Model ◽

Regulatory Network ◽

Regulatory Networks ◽

Sea Urchins ◽

Cell Types ◽

Zygotic Transcription ◽

Gene Regulatory

Sea urchin embryos begin zygotic transcription shortly after the egg is fertilized. Throughout the cleavage stages a series of transcription factors are activated and, along with signaling through a number of pathways, at least 15 different cell types are specified by the beginning of gastrulation. Experimentally, perturbation of contributing transcription factors, signals and receptors and their molecular consequences enabled the assembly of an extensive gene regulatory network model. That effort, pioneered and led by Eric Davidson and his laboratory, with many additional insights provided by other laboratories, provided the sea urchin community with a valuable resource. Here we describe the approaches used to enable the assembly of an advanced gene regulatory network model describing molecular diversification during early development. We then provide examples to show how a relatively advanced authenticated network can be used as a tool for discovery of how diverse developmental mechanisms are controlled and work.

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Estimating Drivers of Cell State Transitions Using Gene Regulatory Network Models

10.1101/089003 ◽

2016 ◽

Author(s):

Daniel Schlauch ◽

Kimberly Glass ◽

Craig P. Hersh ◽

Edwin K. Silverman ◽

John Quackenbush

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Regulatory Networks ◽

Expression Patterns ◽

Cell Types ◽

State Transitions ◽

Chronic Obstructive ◽

Simple Extension ◽

Cell State ◽

Gene Regulatory

AbstractSpecific cellular states are often associated with distinct gene expression patterns. These states are plastic, changing during development, or in the transition from health to disease. One relatively simple extension of this concept is to recognize that we can classify different cell-types by their active gene regulatory networks and that, consequently, transitions between cellular states can be modeled by changes in these underlying regulatory networks. Here we describe MONSTER, MOdeling Network State Transitions from Expression and Regulatory data, a regression-based method for inferring transcription factor drivers of cell state conditions at the gene regulatory network level. As a demonstration, we apply MONSTER to four different studies of chronic obstructive pulmonary disease to identify transcription factors that alter the network structure as the cell state progresses toward the disease-state. Our results demonstrate that MONSTER can find strong regulatory signals that persist across studies and tissues of the same disease and that are not detectable using conventional analysis methods based on differential expression. An R package implementing MONSTER is available at github.com/QuackenbushLab/MONSTER.

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Using linkage logic theory to control dynamics of a gene regulatory network of a chordate embryo

Scientific Reports ◽

10.1038/s41598-021-83045-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kenji Kobayashi ◽

Kazuki Maeda ◽

Miki Tokuoka ◽

Atsushi Mochizuki ◽

Yutaka Satou

Keyword(s):

Gene Regulatory Network ◽

Cell Fate ◽

Biological Networks ◽

Regulatory Network ◽

Cell Types ◽

Sufficient Information ◽

Biological Functions ◽

Cellular Environment ◽

Vertex Set ◽

Gene Regulatory

AbstractLinkage logic theory provides a mathematical criterion to control network dynamics by manipulating activities of a subset of network nodes, which are collectively called a feedback vertex set (FVS). Because many biological functions emerge from dynamics of biological networks, this theory provides a promising tool for controlling biological functions. By manipulating the activity of FVS molecules identified in a gene regulatory network (GRN) for fate specification of seven tissues in ascidian embryos, we previously succeeded in reproducing six of the seven cell types. Simultaneously, we discovered that the experimentally reconstituted GRN lacked information sufficient to reproduce muscle cells. Here, we utilized linkage logic theory as a tool to find missing edges in the GRN. Then, we identified a FVS from an updated version of the GRN and confirmed that manipulating the activity of this FVS was sufficient to induce all seven cell types, even in a multi-cellular environment. Thus, linkage logic theory provides tools to find missing edges in experimentally reconstituted networks, to determine whether reconstituted networks contain sufficient information to fulfil expected functions, and to reprogram cell fate.

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