scholarly journals Genetic Signatures of Evolution of the Pluripotency Gene Regulating Network across Mammals

2020 ◽  
Vol 12 (10) ◽  
pp. 1806-1818
Author(s):  
Yoshinori Endo ◽  
Ken-ichiro Kamei ◽  
Miho Inoue-Murayama
Keyword(s):  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Mammalian Species ◽  
Rapid Evolution ◽  
Regulatory Elements ◽  
Network Evolution ◽  
Pluripotency Gene ◽  
Fundamental Biological Process ◽  
Gene Regulatory ◽  
Taxonomic Groups

Abstract Mammalian pluripotent stem cells (PSCs) have distinct molecular and biological characteristics among species, but to date we lack a comprehensive understanding of regulatory network evolution in mammals. Here, we carried out a comparative genetic analysis of 134 genes constituting the pluripotency gene regulatory network across 48 mammalian species covering all the major taxonomic groups. We report that mammalian genes in the pluripotency regulatory network show a remarkably high degree of evolutionary stasis, suggesting the conservation of fundamental biological process of mammalian PSCs across species. Nevertheless, despite the overall conservation of the regulatory network, we discovered rapid evolution of the downstream targets of the core regulatory elements and specific amino acid residues that have undergone positive selection. Our data indicate development of lineage-specific pluripotency regulating networks that may explain observed variations in some characteristics of mammalian PSCs. We further revealed that positively selected genes could be associated with species’ unique adaptive characteristics that were not dedicated to regulation of PSCs. These results provide important insight into the evolution of the pluripotency gene regulatory network underlying variations in characteristics of mammalian PSCs.

scholarly journals Genetic signatures of evolution of the pluripotency gene regulating network across mammals

2020 ◽  
Author(s):  
Yoshinori Endo ◽  
Ken-ichiro Kamei ◽  
Miho Inoue-Murayama
Keyword(s):  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Mammalian Species ◽  
Rapid Evolution ◽  
Network Evolution ◽  
Downstream Targets ◽  
The Core ◽  
Regulatory Circuit ◽  
Pluripotency Gene ◽  
Gene Regulatory

AbstractMammalian pluripotent stem cells (PSCs) have distinct molecular and biological characteristics, but we lack a comprehensive understanding of regulatory network evolution in mammals. Here, we applied a comparative genetic analysis of 134 genes constituting the pluripotency gene regulatory network across 48 mammalian species covering all the major taxonomic groups. We found evolutionary conservation in JAK-STAT and PI3K-Akt signaling pathways, suggesting equivalent capabilities in self-renewal and proliferation of mammalian PSCs. On the other hand, we discovered rapid evolution of the downstream targets of the core regulatory circuit, providing insights into variations of characteristics. Our data indicate that the variations in the PSCs characteristics may be due to positive selections in the downstream targets of the core regulatory circuit. We further reveal that positively selected genes can be associated with species unique adaptation that is not dedicated to regulation of PSCs. These results provide important insight into the evolution of the pluripotency gene regulatory network underlying variations in characteristics of mammalian PSCs.

scholarly journals Ground rules of the pluripotency gene regulatory network

2017 ◽  
Vol 18 (3) ◽  
pp. 180-191 ◽  
Author(s):  
Mo Li ◽  
Juan Carlos Izpisua Belmonte
Keyword(s):  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Pluripotency Gene ◽  
Gene Regulatory

scholarly journals Gene Regulatory Network Evolution Through Augmenting Topologies

2015 ◽  
Vol 19 (6) ◽  
pp. 823-837 ◽  
Author(s):  
Sylvain Cussat-Blanc ◽  
Kyle Harrington ◽  
Jordan Pollack
Keyword(s):  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Network Evolution ◽  
Gene Regulatory

scholarly journals Extensive NEUROG3 occupancy in the human pancreatic endocrine gene regulatory network

2021 ◽  
Author(s):  
Valérie Schreiber ◽  
Reuben Mercier ◽  
Sara Jímenez ◽  
Tao Ye ◽  
Emmanuel García-Sánchez ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Network ◽  
Beta Cells ◽  
Regulatory Network ◽  
Islet Cell ◽  
Regulatory Elements ◽  
Cell Development ◽  
Bhlh Transcription Factor ◽  
Gene Regulatory ◽  
Endocrine Progenitors

Objective: Mice lacking the bHLH transcription factor (TF) Neurog3 do not form pancreatic islet cells, including insulin secreting beta cells, causing diabetes. In human, homozygous mutations of NEUROG3 manifest with neonatal or childhood diabetes. Despite this critical role in islet cell development, the precise function and downstream genetic programs regulated directly by NEUROG3 remain elusive. We therefore mapped genome-wide NEUROG3 occupancy in human induced pluripotent stem cell (iPSC)-derived endocrine progenitors and determined NEUROG3 dependency of associated genes to uncover direct targets. Methods: We generated a novel hiPSC line (NEUROG3-HA-P2A-Venus), where NEUROG3 is HA-tagged and fused to a self-cleaving fluorescent VENUS reporter. We used the CUT&RUN technique to map NEUROG3 occupancy and epigenetic marks in pancreatic endocrine progenitors (PEP) differentiated from this hiPSC line. We integrated NEUROG3 occupancy data with chromatin status and gene expression in PEPs and their NEUROG3-dependence. In addition, we searched whether NEUROG3 binds type 2 diabetes mellitus (T2DM)-associated variants at the PEP stage. Results: CUT&RUN revealed a total of 863 NEUROG3 binding sites assigned to 1268 unique genes. NEUROG3 occupancy was found at promoters as well as at distant cis-regulatory elements frequently overlapping within PEP active enhancers. De novo motif analyses defined a NEUROG3 consensus binding motif and suggested potential co-regulation of NEUROG3 target genes by FOXA, RFX or PBX transcription factors. Moreover, we found that 22% of the genes downregulated in NEUROG3−/− hESC-derived PEPs are bound by NEUROG3 and thus likely to be directly regulated. NEUROG3 targets include transcription factors known to have important roles in islet cell development or function, such as NEUROD1, PAX4, NKX2-2, SOX4, MLXIPL, LMX1B, RFX3, and NEUROG3 itself. Remarkably, we uncovered that NEUROG3 binds transcriptional regulator genes with enriched expression in human fetal pancreatic alpha (e.g., IRX1, IRX2), beta (e.g., NKX6-1, SMAD9, ISX, TFCP2L1) and delta cells (ERBB4) suggesting that NEUROG3 could control islets subtype programs. Moreover, NEUROG3 targets genes critical for insulin secretion in beta cells (e.g., GCK, ABCC8/KCNJ11, CACNA1A, CHGA, SCG2, SLC30A8 and PCSK1). In addition, we unveiled a panel of ncRNA potentially regulated by NEUROG3. Lastly, we identified several T2DM risk SNPs within NEUROG3 peaks suggesting a possible developmental role of NEUROG3 in T2DM susceptibility. Conclusion: Mapping of NEUROG3 genome occupancy in PEPs uncovers an unexpectedly broad, direct control of the endocrine gene regulatory network (GRN) and raises novel hypotheses on how this master regulator controls islet and beta cell differentiation.

scholarly journals Retrotransposons spread potential cis-regulatory elements during mammary gland evolution

2019 ◽  
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.

scholarly journals Evolution of the mammalian embryonic pluripotency gene regulatory network

2010 ◽  
Vol 107 (46) ◽  
pp. 19955-19960 ◽  
Author(s):  
B. Fernandez-Tresguerres ◽  
S. Canon ◽  
T. Rayon ◽  
B. Pernaute ◽  
M. Crespo ◽  
...  
Keyword(s):  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Pluripotency Gene ◽  
Gene Regulatory

scholarly journals BINDER: computationally inferring a gene regulatory network for Mycobacterium abscessus

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Patrick M. Staunton ◽  
Aleksandra A. Miranda-CasoLuengo ◽  
Brendan J. Loftus ◽  
Isobel Claire Gormley
Keyword(s):  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Likelihood Function ◽  
Computational Modelling ◽  
Regulatory Elements ◽  
Mycobacterium Abscessus ◽  
Sequence Information ◽  
Auxiliary Data ◽  
Regulatory Interactions ◽  
Gene Regulatory

Abstract Background Although many of the genic features in Mycobacterium abscessus have been fully validated, a comprehensive understanding of the regulatory elements remains lacking. Moreover, there is little understanding of how the organism regulates its transcriptomic profile, enabling cells to survive in hostile environments. Here, to computationally infer the gene regulatory network for Mycobacterium abscessus we propose a novel statistical computational modelling approach: BayesIan gene regulatory Networks inferreD via gene coExpression and compaRative genomics (BINDER). In tandem with derived experimental coexpression data, the property of genomic conservation is exploited to probabilistically infer a gene regulatory network in Mycobacterium abscessus.Inference on regulatory interactions is conducted by combining ‘primary’ and ‘auxiliary’ data strata. The data forming the primary and auxiliary strata are derived from RNA-seq experiments and sequence information in the primary organism Mycobacterium abscessus as well as ChIP-seq data extracted from a related proxy organism Mycobacterium tuberculosis. The primary and auxiliary data are combined in a hierarchical Bayesian framework, informing the apposite bivariate likelihood function and prior distributions respectively. The inferred relationships provide insight to regulon groupings in Mycobacterium abscessus. Results We implement BINDER on data relating to a collection of 167,280 regulator-target pairs resulting in the identification of 54 regulator-target pairs, across 5 transcription factors, for which there is strong probability of regulatory interaction. Conclusions The inferred regulatory interactions provide insight to, and a valuable resource for further studies of, transcriptional control in Mycobacterium abscessus, and in the family of Mycobacteriaceae more generally. Further, the developed BINDER framework has broad applicability, useable in settings where computational inference of a gene regulatory network requires integration of data sources derived from both the primary organism of interest and from related proxy organisms.

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