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1. Systems genome, Gene Activity Networks, and Recurrent Activity Motifs in control of genome homeostasis; a role of nuclear FGFR1

   J. Diehl, N. Manoj (January 2022, 8th Genetics, Genomics, and Bioinformatics Annual Research Day at the University at Buffalo)

   During transition of human Neural Progenitor Cells (NPC) to Neuronal Committed Cells (NCC) activities of 4706 genes change their activities. These changes obey the Gaussian principle whereby the majority are moderate and few represent extreme up- or down-regulations. Inhibition of pan-ontogenic nuclear Fibroblast Growth Factor Receptor 1 (nFGFR1) signaling, which mediates the NPC to NCC differentiation, affected the activities of hundreds of genes in NPC and in NCC. Our new results show that nFGFR1 acts as a Band-Path filter that maintains global genome function within a homeostatic range by diminishing extreme changes and promoting moderate changes. To elaborate on the underlying mechanism, we analyzed Pearson correlation among the genes of the regulated genome. The majority of 4007 gene activities were highly coordinated and their frequencies were increased during the NPC to NCC transition while the low coordinated genes were decreased. The frequencies of high and low coordinated genes were affected by the inhibition of endogenous nFGFR1 and by the overexpression of constitutively active nFGFR1. Analysis of Gene Activity Networks (GANs) formed by the most coordinated neurodevelopmental genes showed that NPC to NCC transition is accompanied by a deconstruction of NPC GANs and construction of new NCC GANs and that the formation of GANs is largely dependent on the endogenous levels of nFGFR1. Within the GANs we identified several overrepresented Recurring Correlation Motifs (RCM) which undergo frequency redistribution during differentiation. The high complexity motifs (with a high number of connections) increased during GANs’ construction and decreased during GANs’ deconstruction. The ability of the RCM to counteract excessive gene activity oscillation during differentiation was analyzed by modelling their function as electrical RLC equivalent networks with genes serving as inductors (L) and the equivalent Spring-mass oscillator model. In RLC circuits, where the reduced inductance value from star network arrangement dampens the oscillations, increased motifs complexity dampens down the oscillations in the individual nodes (genes) activities as the network transits between different activity levels. In conclusion, deselection of low complexity of motifs and selection of more complex motifs by nFGFR1 serve to maintain the genome homeostasis during development. A Proportional–Integral–Derivative (PID) controller model with the RLC lumped element equivalents is proposed employing nFGFR1 feedback as a control system of the ontogenic gene programs. 

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2. Systems Genome: Coordinated Gene Activity Networks, Recurring Coordination Modules, and Genome Homeostasis in Developing Neurons

   https://doi.org/10.3390/ijms25115647  

   Dhiman, Siddhartha; Manoj, Namya; Liput, Michal; Sangwan, Amit; Diehl, Justin; Balcerak, Anna; Sudhakar, Sneha; Augustyniak, Justyna; Jornet, Josep M; Bae, Yongho; et al (June 2024, International Journal of Molecular Sciences)

   As human progenitor cells differentiate into neurons, the activities of many genes change; these changes are maintained within a narrow range, referred to as genome homeostasis. This process, which alters the synchronization of the entire expressed genome, is distorted in neurodevelopmental diseases such as schizophrenia. The coordinated gene activity networks formed by altering sets of genes comprise recurring coordination modules, governed by the entropy-controlling action of nuclear FGFR1, known to be associated with DNA topology. These modules can be modeled as energy-transferring circuits, revealing that genome homeostasis is maintained by reducing oscillations (noise) in gene activity while allowing gene activity changes to be transmitted across networks; this occurs more readily in neuronal committed cells than in neural progenitors. These findings advance a model of an “entangled” global genome acting as a flexible, coordinated homeostatic system that responds to developmental signals, is governed by nuclear FGFR1, and is reprogrammed in disease. 

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3. Analysis of the genome-editing activity of microinjected CRISPR/Cas9 ribonucleoprotein complexes in Daphnia pulex

   https://doi.org/10.17912/micropub.biology.001310  

   Maar, Megan E; Miller, Jay C; Lynch, Michael; Zelhof, Andrew C (October 2024, microPublication biology)

   Although Daphnia is a widely used model organism with a completely sequenced genome, molecular tools for analyzing specific gene functions are still being developed. Progress has been made in developing CRISPR/Cas9 gene editing in Daphnia. However, the gene-editing activity of injected ribonucleoprotein complexes (RNPs), the success of co-injected RNPs with different gRNAs, and the heritability of mutations in asexual progeny need further investigation. Here, we show prolonged Cas9 RNP activity past the one-cell stage injected individuals, leading to a wide range of somatic mutations, and germline mosaicism of heritable biallelic mutations. 

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4. A genome-wide copper-sensitized screen identifies novel regulators of mitochondrial cytochrome c oxidase activity

   https://doi.org/10.1016/j.jbc.2021.100485  

   Garza, Natalie M; Griffin, Aaron T; Zulkifli, Mohammad; Qiu, Chenxi; Kaplan, Craig D; Gohil, Vishal M (January 2021, Journal of Biological Chemistry)
5. Genome-Scale Architecture of Small Molecule Regulatory Networks and the Fundamental Trade-Off between Regulation and Enzymatic Activity

   https://doi.org/10.1016/j.celrep.2017.08.066  

   Reznik, Ed; Christodoulou, Dimitris; Goldford, Joshua E.; Briars, Emma; Sauer, Uwe; Segrè, Daniel; Noor, Elad (September 2017, Cell Reports)