The ProCisTranomic of human ETS family
Ontology highlight
ABSTRACT:
INSTRUMENT(S): timsTOF Pro 2
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Markku Varjosalo
PROVIDER: MSV000096095 | MassIVE | Tue Oct 15 06:59:00 BST 2024
REPOSITORIES: MassIVE
Similar Datasets
Project description:The Nuclear Factor I (NFI) family of transcription factors (TFs) plays key roles in cellular differentiation, proliferation, and homeostasis. As such, NFI family members engage in large number of interactions with other proteins and the chromatin. However, despite their well-established significance, the NFIs interactomes, their dynamics, and their functions have not been comprehensively examined. Here, we employed complementary omics-level techniques, i.e. interactomics (affinity purification mass spectrometry (AP-MS) and proximity-dependent biotinylation (BioID)), and chromatin immunoprecipitation sequencing (ChIP-Seq), to obtain a comprehensive view of the NFI proteins and their interactions. Our analyses included all four main NFI family members, and a less studied short isoform of NFIB (NFIB4), which lacks the DNA binding domain. We observed that, despite exhibiting some redundancy, each family member had unique high-confidence interactors and target genes, highlighting distinct roles within the transcriptional regulatory networks. The study revealed that NFIs interact with a large number of other TFs to co-regulate a broad range of regulatory networks and cellular processes. Notably, time-dependent proximity-labeling unveiled a highly dynamic nature of NFI protein-protein interaction networks and hinted at temporal modulation of NFI interactions. Furthermore, gene ontology (GO) enrichment analysis of NFI interactome and targetome revealed the involvement of NFIs in transcriptional regulation, chromatin organization, and cellular signaling pathways, and pathways related with cancer. Additionally, we observed that NFIB4 engages with proteins associated with mRNA regulation, which suggests that NFIs have roles beyond traditional DNA binding and transcriptional modulation. We propose that NFIs serve as pioneering TFs, playing critical roles in regulating other TFs and influencing a wide range of cellular processes. These insights into NFI protein-protein interactions and their dynamic, context-dependent nature provide a deeper understanding of gene regulation mechanisms and hint at the role of NFIs as master regulators.
2024-06-26 | MSV000095163 | MassIVE
Project description:Bianconi2012 - EGFR and IGF1R pathway in lung cancer
EGFR and IGF1R pathways play a key role in various human cancers and are crucial for tumour transformation and survival of malignant cells. High EGFR and IGF1R expression and activity has been associated with multiple aspects of cancer progression including tumourigenesis, metastasis, resistance to chemotherapeutics and other molecularly targeted drugs. Here, the biological relationship between the proteins involved in EGFR and IGF1R pathways and the downstream MAPK and PIK3 networks has been modelled to study the time behaviour of the overall system, and the functional interdependencies among the receptors, the proteins and kinases involved.
This model is described in the article:
Computational model of EGFR and IGF1R pathways in lung cancer: a Systems Biology approach for Translational Oncology.
Bianconi F, Baldelli E, Ludovini V, Crinò L, Flacco A, Valigi P.
Biotechnol Adv. 2012 Jan-Feb;30(1):142-53.
Abstract:
In this paper we propose a Systems Biology approach to understand the molecular biology of the Epidermal Growth Factor Receptor (EGFR, also known as ErbB1/HER1) and type 1 Insulin-like Growth Factor (IGF1R) pathways in non-small cell lung cancer (NSCLC). This approach, combined with Translational Oncology methodologies, is used to address the experimental evidence of a close relationship among EGFR and IGF1R protein expression, by immunohistochemistry (IHC) and gene amplification, by in situ hybridization (FISH) and the corresponding ability to develop a more aggressive behavior. We develop a detailed in silico model, based on ordinary differential equations, of the pathways and study the dynamic implications of receptor alterations on the time behavior of the MAPK cascade down to ERK, which in turn governs proliferation and cell migration. In addition, an extensive sensitivity analysis of the proposed model is carried out and a simplified model is proposed which allows us to infer a similar relationship among EGFR and IGF1R activities and disease outcome.
This model is hosted on BioModels Database
and identified by: MODEL1209230000
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To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models
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To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
2024-09-02 | BIOMD0000000427 | BioModels
Project description:To dissect Cohesin-independent mechanisms that compartmentalize the mammalian genome, we combined super-resolution imaging and high-resolution chromatin interactome, chromatin binding and accessibility and RNA sequencing analysis. We found that the bromodomain and extra-terminal domain (BET) family protein BRD2 is one key regulator to promote compartmental interactions in the absence of Cohesin. We also identified competitive, rather than cooperative relationship between BET family proteins in shaping the 3D genome organization. This study uncovers new mechanisitc insights on the 3D organization of the mammalian genome.
2022-02-09 | GSE163729 | GEO
Project description:The ETO-family transcriptional corepressors, including ETO, ETO2 and MTGR1, are all involved in leukemia-causing chromosomal translocations. In every case, an ETO-family corepressor acquires a DNA-binding domain (DBD) to form a typical transcription factor – the DBD binds to target genes, while the ETO moiety contributes essentially to its transcriptional property. A direct comparative study of these “homologous” fusion transcription factors may clarify their similarities and differences in regulating transcription and leukemogenesis. Here, we performed a side-by-side comparison between AML1-ETO and ETO2-GLIS2, the most common fusion proteins in the M2 and M7 subtypes of acute myeloid leukemia, respectively, by inducible expression of them in U937 leukemia cells. We found that, although AML1-ETO and ETO2-GLIS2 can use their own DBDs (i.e., the Runt domain of AML1 and the zinc finger domain of GLIS2) to bind DNA, they actually share a large proportion of genome-wide binding regions dependent on other cooperative transcription factors such as ETS- and CEBP-family proteins. Functionally, AML1-ETO acts as either transcriptional repressor or activator, whereas ETO2-GLIS2 mainly acts as an activator. The repressor-versus-activator functions of AML1-ETO is determined by the abundance of cooperative transcription factors/cofactors on the target genes. Through these mechanisms, AML1-ETO and ETO2-GLIS2 differentially regulate several key transcription factors that are essential for myeloid differentiation. Indeed, AML1-ETO inhibits myeloid differentiation of U937 cells, whereas ETO2-GLIS2 facilitates it. Taken together, this study is the first direct comparative study between AML1-ETO and ETO2-GLIS2 in the same cellular context, and the results provide new insights into the context-dependent transcriptional regulatory mechanisms that may underlie how these seemingly “homologous” fusion transcription factors exert distinct functions to drive different subtypes of leukemia.
2022-07-05 | GSE207217 | GEO
Project description:The ETO-family transcriptional corepressors, including ETO, ETO2 and MTGR1, are all involved in leukemia-causing chromosomal translocations. In every case, an ETO-family corepressor acquires a DNA-binding domain (DBD) to form a typical transcription factor – the DBD binds to target genes, while the ETO moiety contributes essentially to its transcriptional property. A direct comparative study of these “homologous” fusion transcription factors may clarify their similarities and differences in regulating transcription and leukemogenesis. Here, we performed a side-by-side comparison between AML1-ETO and ETO2-GLIS2, the most common fusion proteins in the M2 and M7 subtypes of acute myeloid leukemia, respectively, by inducible expression of them in U937 leukemia cells. We found that, although AML1-ETO and ETO2-GLIS2 can use their own DBDs (i.e., the Runt domain of AML1 and the zinc finger domain of GLIS2) to bind DNA, they actually share a large proportion of genome-wide binding regions dependent on other cooperative transcription factors such as ETS- and CEBP-family proteins. Functionally, AML1-ETO acts as either transcriptional repressor or activator, whereas ETO2-GLIS2 mainly acts as an activator. The repressor-versus-activator functions of AML1-ETO is determined by the abundance of cooperative transcription factors/cofactors on the target genes. Through these mechanisms, AML1-ETO and ETO2-GLIS2 differentially regulate several key transcription factors that are essential for myeloid differentiation. Indeed, AML1-ETO inhibits myeloid differentiation of U937 cells, whereas ETO2-GLIS2 facilitates it. Taken together, this study is the first direct comparative study between AML1-ETO and ETO2-GLIS2 in the same cellular context, and the results provide new insights into the context-dependent transcriptional regulatory mechanisms that may underlie how these seemingly “homologous” fusion transcription factors exert distinct functions to drive different subtypes of leukemia.
2022-07-05 | GSE207216 | GEO
Project description:Mitotic bookmarking transcription factors (TFs) are thought to mediate rapid and accurate post-mitotic gene reactivation. However, the loss of individual bookmarking TFs often leads to the deregulation of only a small proportion of their mitotic targets, raising doubts on the significance and importance of their bookmarking function. Here, we used targeted proteomics of the mitotic bookmarking TF ESRRB, an orphan nuclear receptor, to discover an unexpected redundancy among members of the protein superfamily of nuclear receptors. Focusing on the nuclear receptor NR5A2, which together with ESRRB is essential in maintaining pluripotency in mouse embryonic stem cells, we demonstrate conjoint bookmarking activity of both factors on promoters and enhancers of a large fraction of active genes, particularly the most rapidly and strongly reactivated ones. Upon fast and simultaneous degradation of both factors during mitotic exit, hundreds of mitotic targets of ESRRB/NR5A2, including key players of the pluripotency network, display attenuated transcriptional reactivation. We propose that redundancy in mitotic bookmarking TFs, especially nuclear receptors, confers robustness to the reestablishment of gene regulatory networks after mitosis.
2023-11-20 | PXD038950 | Pride
Project description:This model is from the article:
Systems biology analysis of programmed cell death
Shani Bialik, Einat Zalckvar, Yaara Ber, Assaf D. Rubinstein, Adi Kimchi Trends in Biochemical Sciences
Volume 35, Issue 10, 556-564, 27 May 2010 20537543
,
Abstract:
Systems biology, a combined computational and experimental approach to analyzing complex biological systems, has recently been applied to understanding the pathways that regulate programmed cell death. This approach has become especially crucial because recent advances have resulted in an expanded view of the network, to include not just a single death module (apoptosis) but multiple death programs, including programmed necrosis and autophagic cell death. Current research directions in the systems biology field range from quantitative analysis of subprocesses of individual death pathways to the study of interconnectivity among the various death modules of the larger network. These initial studies have provided great advances in our understanding of programmed cell death and have important clinical implications for drug target research.
Brief Note about the model:
This model is an export of 26 SPIKE
Apoptosis Networks to SBML format.
This is a pathway model (not quantitative model) of Apoptosis.
Apoptosis, or type I cell death, is a form of programmed cell death
characterized by fragmentation of the cytoplasm and nucleus, chromatin
condensation and fragmentation, cytoskeletal collapse, membrane
blebbing, and finally, disintegration of the cell into apoptotic
bodies, which are engulfed by adjacent cells, thereby avoiding an
inflammatory response. It serves to model tissues during embryonic
development, to regulate cell number by eliminating excess cells, and
to remove damaged, mutated or infected cells. Defective or excessive
apoptosis can lead to cancer or autoimmune and degenerative diseases,
respectively. Apoptosis is executed by a family of cysteine proteases,
the caspases, which function in a proteolytic cascade that is
initiated by either the intrinsic mitochondrial-based pathway leading
to apoptosome formation, or the extrinsic pathway, which involves
activation of death receptors by their extracellular ligands to form
the DISC. The most distal caspases, known as the executioner caspases,
cleave numerous cellular substrates, thereby leading to specific
dismantling of the cell. Apoptosis is regulated by multiple proteins
at several levels, including the Bcl-2 family, which regulate the
release of apoptogenic factors from the mitochondria, and the IAP
family, which regulate caspase activity, and is countered by survival
signals eminating from the NF-kB signaling pathway. Although most of
the regulation occurs at the post-translational level, involving
protein-protein interactions, proteolysis, changes in subcellular
localization and phosphorylation, transcriptional control, such as by
p53, can also modulate the expression levels of several key apoptotic
proteins.
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.
.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1107050000 | BioModels
Project description:High-resolution mass spectrometry analysis of Interleukin 2 (IL-2) and Janus kinase (JAK) controlled protein phosphorylations in cytotoxic T lymphocytes (CTL) revealed JAKs coupled IL-2 receptors to diverse and complex serine/threonine kinase-substrate networks. These involved intricate, co-ordinated phosphorylation of transcription factors, chromatin regulators within the nuclear environment, cytosolic mRNA translational machinery, regulators of GTPases, vesicle trafficking proteins and the actin and microtubule cytoskeleton. We also identified an IL-2-JAK independent SRC family Tyr kinase controlled signaling network that regulates ~10% of the CTL phosphoproteome. One key signaling pathway in CTL is mediated by phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and the serine/threonine kinase AKT. Strikingly, SRC family kinase dependent but JAK independent signaling controlled PIP3 levels and AKT activity in CTL. IL-2-JAK controlled signaling pathways thus coordinate with IL-2 independent networks of protein phosphorylation to program CTL fate.
2016-08-25 | PXD004645 | Pride
Project description:Chromatin modulation provides a key checkpoint for controlling cell cycle regulated gene networks. The replicative canonical histone genes are one such gene family under tight regulation during cell division. These genes are most highly expressed during S phase when histones are needed to chromatinize the new DNA template. While this fact has been known for a while, limited knowledge exists about the specific chromatin regulators controlling their temporal expression during cell cycle. Since histones and their associated mutations are emerging as major players in diseases such as cancer, identifying the chromatin factors modulating their expression is critical. The histone lysine tri-demethylase KDM4A is regulated over cell cycle and plays a direct role in DNA replication timing, site-specific rereplication, and DNA amplifications during S phase. Here, we establish an unappreciated role for the catalytically active KDM4A in directly regulating canonical replicative histone gene networks during cell cycle. Of interest, we further demonstrate that KDM4A interacts with proteins controlling histone expression and RNA processing. Together, this study provides a new function for KDM4A in modulating canonical histone gene expression.
2021-10-27 | GSE154684 | GEO
Project description:The Ten-eleven translocation (TET) family of dioxygenases can mediate cytosine demethylation by catalyzing the oxidation of 5-methylcytosine (5mC). TET-mediated DNA demethylation controls the proper differentiation of embryonic stem cells and TET proteins display functional redundancy during early gastrulation. However, it is unclear if TET proteins have functional significance in mammalian skeletal development. Here, we report that Tet deficiency in mesoderm mesenchymal stem cells results in severe defects of bone development. The existence of any single Tet gene allele can support early bone formation, suggesting a potential functional redundancy of TET proteins. Integrative analyses of RNA-seq, Whole Genome Bisulfite Sequencing (WGBS) and Assay for Transposase-Accessible Chromatin (ATAC-seq) demonstrate that TET-mediated demethylation increases the chromatin accessibility of target genes by RUNX2 and facilities RUNX2-regulated transcription. In addition, TET proteins interact with RUNX2 through their catalytic domain to regulate cytosine methylation around RUNX2 binding region. The catalytic domain is indispensable for TET proteins to regulate RUNX2 transcription activity on its target genes and to regulate bone development. These results demonstrate that TET proteins function redundantly to regulate RUNX2 activity via dual mechanisms and maintain skeletal homeostasis.
2022-07-07 | GSE174047 | GEO