Evolutionary Computations and Modular Organization of the Gene Regulatory Regions

Author(s):  
Alexander Spirov ◽  
Ekaterina Myasnikova
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Tarang K. Mehta ◽  
Christopher Koch ◽  
Will Nash ◽  
Sara A. Knaack ◽  
Padhmanand Sudhakar ◽  
...  

Abstract Background Seminal studies of vertebrate protein evolution speculated that gene regulatory changes can drive anatomical innovations. However, very little is known about gene regulatory network (GRN) evolution associated with phenotypic effect across ecologically diverse species. Here we use a novel approach for comparative GRN analysis in vertebrate species to study GRN evolution in representative species of the most striking examples of adaptive radiations, the East African cichlids. We previously demonstrated how the explosive phenotypic diversification of East African cichlids can be attributed to diverse molecular mechanisms, including accelerated regulatory sequence evolution and gene expression divergence. Results To investigate these mechanisms across species at a genome-wide scale, we develop a novel computational pipeline that predicts regulators for co-extant and ancestral co-expression modules along a phylogeny, and candidate regulatory regions associated with traits under selection in cichlids. As a case study, we apply our approach to a well-studied adaptive trait—the visual system—for which we report striking cases of network rewiring for visual opsin genes, identify discrete regulatory variants, and investigate their association with cichlid visual system evolution. In regulatory regions of visual opsin genes, in vitro assays confirm that transcription factor binding site mutations disrupt regulatory edges across species and segregate according to lake species phylogeny and ecology, suggesting GRN rewiring in radiating cichlids. Conclusions Our approach reveals numerous novel potential candidate regulators and regulatory regions across cichlid genomes, including some novel and some previously reported associations to known adaptive evolutionary traits.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sebastian Carrasco Pro ◽  
Katia Bulekova ◽  
Brian Gregor ◽  
Adam Labadorf ◽  
Juan Ignacio Fuxman Bass

Abstract Single nucleotide variants (SNVs) located in transcriptional regulatory regions can result in gene expression changes that lead to adaptive or detrimental phenotypic outcomes. Here, we predict gain or loss of binding sites for 741 transcription factors (TFs) across the human genome. We calculated ‘gainability’ and ‘disruptability’ scores for each TF that represent the likelihood of binding sites being created or disrupted, respectively. We found that functional cis-eQTL SNVs are more likely to alter TF binding sites than rare SNVs in the human population. In addition, we show that cancer somatic mutations have different effects on TF binding sites from different TF families on a cancer-type basis. Finally, we discuss the relationship between these results and cancer mutational signatures. Altogether, we provide a blueprint to study the impact of SNVs derived from genetic variation or disease association on TF binding to gene regulatory regions.


2015 ◽  
Vol 23 ◽  
pp. A196
Author(s):  
C.G. Boer ◽  
M. de Kruijf ◽  
L. Broer ◽  
A. Hofman ◽  
A.G. Uitterlinden ◽  
...  

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Ji Hun Kim ◽  
Tao Zhang ◽  
Nicholas C. Wong ◽  
Nadia Davidson ◽  
Jovana Maksimovic ◽  
...  

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 602-602
Author(s):  
Courtney L Jones ◽  
Teena Bhatla ◽  
Jinhua Wang ◽  
Wallace Bourgeois ◽  
Bitterman S Danielle ◽  
...  

Abstract Introduction The prognosis for children with acute lymphoblastic leukemia who relapse is poor and discovery of the underlying mechanisms that lead to drug resistance is a top priority. Relapsed blasts have intrinsic chemoresistance compared to diagnosis blasts especially to glucocorticoids (Klumper et. al, 1995). Furthermore, resistance to glucocorticoids is associated with a poor prognosis in childhood ALL (Dördelmann M et. al, Blood 1999, Schmiegelow K et. al, Leukemia 2001, Tissing WJ et. al, Leukemia 2003). We have previously identified recurrent deletions with concordant decreased gene expression in TBL1XR1 in 10.7% of patients at relapse (Hogan et. al, 2011). TBL1XR1 codes for the TBLR1 protein which is responsible for the dismissal and degradation of nuclear corepressor (N-CoR) complex proteins including N-CoR1, SMRT, GPS2, and histone deacetylases (HDAC) (Perissi V et. al, Cell 2004). We hypothesized that TBL1XR1 deletions may result in resistance to glucocorticoid agonist, prednisolone through up-regulation of N-CoR complex proteins. Methods B-precursor ALL cell lines Reh, and RS4;11 were transduced with lentiviral constructs containing control and TBL1XR1 targeting shRNAs. Knockdown was confirmed by RT-PCR and western blotting. Stable cell lines were treated with prednisolone, doxorubicin, 6-thioguanine, or etoposide for 24-48 hours. Cell viability and apoptosis were measured by cell titer glo luminescence assay (promega) and annexin V-PE and 7-Amino-actinomycin D (7AAD) staining (Annexin V-PE Apoptosis Detection Kit, BD Pharmingen, San Diego, CA, USA) respectively. To determine changes in global gene expression by TBL1XR1 knockdown, stable Reh cell lines were treated with prednisolone or vehicle for 8 hours and then collected for RNA extraction (Qiagen, RNeasy mini kit) and microarray analysis. Microarray data was validated by RT-PCR. To elucidate the mechanism of resistance we performed small-scale biochemical fractionation and chromatin immunoprecipitation (ChIP) detecting levels of glucocorticoid receptor (GR), TBLR1, N-CoR1, and HDAC3 residing on the chromatin as well as gene specific glucocorticoid response elements (GREs). Results In this study, we demonstrate that knockdown of TBL1XR1 results in resistance to the glucocorticoid agonist prednisolone but not other classes of chemotherapeutic agents. We discovered that 51 of the 117 genes induced by prednisolone in control cells had decreased induction of at least 50%. We validated a subset of prednisolone induced genes including, GILZ, TXNIP, ZEB1, ST6GALNAC3, IL21R, and CCPG1 by RT-PCR. To explore the mechanism of TBL1XR1 mediated decrease in GR signaling we determined the effect of TBL1XR1 depletion of GR recruitment to total bulk chromatin. In TBL1XR1 knockdown cells, no GR was detected in the chromatin associated fractions in vehicle or prednisolone treatment conditions, despite similar levels of GR protein between control and TBL1XR1 knock down lines. We show that the decreased GR levels is associated with an increased level of NCoR1 detected in the chromatin fraction of TBLR1 depleted cells; however no change in HDAC3 levels were observed. We confirmed these results by interrogating the gene regulatory regions of GILZ and TXNIP by ChIP. In TBL1XR1 depleted lines a decrease in GR occupancy in prednisolone stimulated cells was observed compared to control lines. We also observed increased levels of N-CoR1, and HDAC3 occupying these GREs. To interrogate the functional relationship between increased NCoR1 and HDAC3 levels on the gene regulatory region as a result of TBL1XR1 knockdown we depleted NCoR1 or inhibited HDAC3 using a pan HDAC inhibitor SAHA and examined the impact of prednisolone treatment on cell viability and induction of GILZ. We found that upon NCoR1 depletion or HDAC inhibition, TBL1XR1 knockdown line was no longer resistant to prednisolone and the induction of GILZ was restored. Conclusions Reduction of TBL1XR1 results in prednisolone resistance in ALL by decreasing GR occupancy on gene regulatory regions through the upregulation of the NCoR co-repressor complex at these sites. Our work and others has provided insight into the importance of transcription regulatory complexes in steroid resistance in ALL (and perhaps other malignancies) as well as opportunities for novel therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.


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