scholarly journals EPEN-16. TRANSCRIPTIONAL REGULATORY CIRCUITRIES AS MOLECULAR TARGETS IN EPENDYMOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii310-iii310
Author(s):  
Kelsey Bertrand ◽  
Stephen Mack ◽  
Donald W Parsons

Abstract Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas comprise histologically similar tumor entities driven by distinct molecular mechanisms, such as fusion oncoproteins, genome-wide chromosomal instability, or disruption of DNA methylation patterns. Despite these differences, ependymomas resist chemotherapy and lack available targeted agents for clinical trial development. Based on our previous findings, we hypothesized that mapping chromatin landscapes and super enhancers (SE) could uncover transcriptional dependencies as targets for therapy (Mack, Pajtler, Chavez et al., Nature, 2018). To functionally test the requirement of these SE genes for ependymoma cellular growth, we designed a pooled RNA interference screen against 267 SE associated genes. Our screen was performed in one C11ORF95-RELA-fusion model and two PF-EPN-A models as controls in biological triplicates. As an indication that our screen was successful, positive controls scored among lead hits including KIF11, BUB1B, PHF5A and MYC. Importantly, we identified many subtype specific dependencies in both C11ORF95-RELA-fusion and PF-EPN-A models, thus revealing novel pathways that potentially govern subgroup-specific ependymoma cell growth. Further, several candidates detected across all ependymoma lines were also identified as pan-cancer dependencies or glioma/glioblastoma specific essential genes from the DepMap Cancer Dependency Gene Resource. Our findings reveal novel targets and pathways that are essential for ependymoma cell growth, which may provide new insight into therapeutic strategies against these aggressive brain tumors.

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i15-i15
Author(s):  
Kelsey Bertrand ◽  
Stephen Mack

Abstract Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas comprise histologically similar tumor entities driven by distinct molecular mechanisms, such as fusion oncoproteins, genome-wide chromosomal instability, or disruption of DNA methylation patterns. Despite these differences, ependymomas resist chemotherapy and lack available targeted agents for clinical trial development. Based on our previous findings, we hypothesized that mapping chromatin landscapes and super enhancers (SE) could uncover transcriptional dependencies as targets for therapy (Mack, Pajtler, Chavez et al., Nature, 2018). To functionally test the requirement of these SE genes for ependymoma cellular growth, we designed a pooled RNA interference screen against 267 SE associated genes. Our screen was performed in one C11ORF95-RELA-fusion model and two PF-EPN-A models as controls in biological triplicates. As an indication that our screen was successful, positive controls scored among lead hits including KIF11, BUB1B, PHF5A and MYC. Importantly, we identified many subtype specific dependencies in both C11ORF95-RELA-fusion and PF-EPN-A models, thus revealing novel pathways that potentially govern subgroup-specific ependymoma cell growth. Further, several candidates detected across all ependymoma lines were also identified as pan-cancer dependencies or glioma/glioblastoma specific essential genes from the DepMap Cancer Dependency Gene Resource. Our findings reveal novel targets and pathways that are essential for ependymoma cell growth, which may provide new insight into therapeutic strategies against these aggressive brain tumors.


2021 ◽  
Author(s):  
Shouhartha Choudhury

Abstract Background: The inhibitor of differentiation (ID) family of TF’s accumulated the result of development. This subgroup of bHLH TF’s is an inverse regulator that acquires to constrain segregation and stimulate proliferation. The ID family of bHLH TF's control the reactions of homodimer and heterodimer by motions of E proteins (Class A) and tissue-specific (Class B) bHLH domain. A recent report suggested ID genes act to enhance the proliferative potential of tumour astrocytes. Those reports supported ID genes are mighty regulators in tumour-angiogenesis and govern the malignant response of glial tumours. So, I performed bioinformatics and computational application to the current knowledge of the ID family in two different genomes. Results: My finding supported the number of ID1-ID4 genes and their encoded proteins present in two isolated organisms. Therefore, I documented the molecular functions and mechanisms linked with the ID family of TF’s in mammals. Those mechanisms assume the ID1-ID4 of bHLH domains reveals an inherent role during differentiation, cell-cycle regulation, and cellular growth. Conclusion: My finding data provided the foundation of ID1-ID4 genes in glial tumours. Also, the numerous molecular mechanisms described the hallmark of glial development.


2009 ◽  
Vol 05 (0) ◽  
pp. 27
Author(s):  
Clara C Elbers ◽  
Marcel GM Wolfs ◽  
Timon W van Haeften ◽  
◽  
◽  
...  

The incidence of type 2 diabetes is rising rapidly worldwide, mainly due to the increase in the incidence of obesity. Both obesity and type 2 diabetes are complex genetic traits, but they share some non-genetic risk factors. Hence, it is tempting to speculate that susceptibility to type 2 diabetes and obesity may also involve shared underlying genetic factors acting on common molecular mechanisms. Recent genome-wide association (GWA) studies identified 17 common loci for obesity and 19 common loci for type 2 diabetes. This article explores whether the susceptibility loci for type 2 diabetes and obesity can indicate potential overlapping mechanisms in the disorders. In addition, we touch on the challenges regarding follow-up of confirmed GWA signals, as well as alternative approaches to analysing GWA data to a fuller potential.


Genome ◽  
2019 ◽  
Vol 62 (12) ◽  
pp. 807-816 ◽  
Author(s):  
Mina Yu ◽  
Junjie Yu ◽  
Huijuan Cao ◽  
Mingli Yong ◽  
Yongfeng Liu

In filamentous fungi, the conserved transcription factors play important roles in multiple cellular and developmental processes. The GATA proteins, a family of GATA-binding zinc finger transcription factors, play diverse functions in fungi. Ustilaginoidea virens is an economically important pathogen-causing rice false smut worldwide. To gain additional insight into the cellular and molecular mechanisms of this pathogen, in this study, we identified and functionally characterized seven GATA proteins from the U. virens genome (UvGATA). Sequences analysis indicated that these GATA proteins are divided into seven clades. The proteins in each clade contained conserved clade-specific sequences and structures, thus leading to the same motif serving different purposes in various contexts. The expression profiles of UvGATA genes at different infection stages and under H2O2 stress were detected. Results showed that the majority of UvGATA genes performed functions at both processes, thereby confirming the roles of these genes in pathogenicity and reactive oxygen species stress tolerance. This study provided an important starting point to further explore the biological functions of UvGATA genes and increased our understanding of their potential transcriptional regulatory mechanisms in U. virens.


2020 ◽  
Vol 27 ◽  
Author(s):  
Giulia De Riso ◽  
Sergio Cocozza

: Epigenetics is a field of biological sciences focused on the study of reversible, heritable changes in gene function not due to modifications of the genomic sequence. These changes are the result of a complex cross-talk between several molecular mechanisms, that is in turn orchestrated by genetic and environmental factors. The epigenetic profile captures the unique regulatory landscape and the exposure to environmental stimuli of an individual. It thus constitutes a valuable reservoir of information for personalized medicine, which is aimed at customizing health-care interventions based on the unique characteristics of each individual. Nowadays, the complex milieu of epigenomic marks can be studied at the genome-wide level thanks to massive, highthroughput technologies. This new experimental approach is opening up new and interesting knowledge perspectives. However, the analysis of these complex omic data requires to face important analytic issues. Artificial Intelligence, and in particular Machine Learning, are emerging as powerful resources to decipher epigenomic data. In this review, we will first describe the most used ML approaches in epigenomics. We then will recapitulate some of the recent applications of ML to epigenomic analysis. Finally, we will provide some examples of how the ML approach to epigenetic data can be useful for personalized medicine.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Karolina Stępniak ◽  
Magdalena A. Machnicka ◽  
Jakub Mieczkowski ◽  
Anna Macioszek ◽  
Bartosz Wojtaś ◽  
...  

AbstractChromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.


2021 ◽  
Vol 7 (3) ◽  
pp. eabd9036
Author(s):  
Sara Saez-Atienzar ◽  
Sara Bandres-Ciga ◽  
Rebekah G. Langston ◽  
Jonggeol J. Kim ◽  
Shing Wan Choi ◽  
...  

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.


Plants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 706
Author(s):  
Antonio J. Moreno-Pérez ◽  
Raquel Martins-Noguerol ◽  
Cristina DeAndrés-Gil ◽  
Mónica Venegas-Calerón ◽  
Rosario Sánchez ◽  
...  

Histone modifications are of paramount importance during plant development. Investigating chromatin remodeling in developing oilseeds sheds light on the molecular mechanisms controlling fatty acid metabolism and facilitates the identification of new functional regions in oil crop genomes. The present study characterizes the epigenetic modifications H3K4me3 in relationship with the expression of fatty acid-related genes and transcription factors in developing sunflower seeds. Two master transcriptional regulators identified in this analysis, VIV1 (homologous to Arabidopsis ABI3) and FUS3, cooperate in the regulation of WRINKLED 1, a transcriptional factor regulating glycolysis, and fatty acid synthesis in developing oilseeds.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Helena R. R. Wells ◽  
Fatin N. Zainul Abidin ◽  
Maxim B. Freidin ◽  
Frances M. K. Williams ◽  
Sally J. Dawson

AbstractTinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. From a total of 172,608 UK Biobank participants who answered questions on tinnitus we performed a case–control genome-wide association study for self-reported tinnitus. Final sample size used in association analysis was N = 91,424. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p = 1.7E−08), rs4900545 (p = 1.8E−08) and 14:103042287_CT_C (p = 3.50E−08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p < 1E−06.


Sign in / Sign up

Export Citation Format

Share Document