scholarly journals Core regulatory circuitries in defining cancer cell identity across the malignant spectrum

Open Biology ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 200121
Author(s):  
Leila Jahangiri ◽  
Loukia Tsaprouni ◽  
Ricky M. Trigg ◽  
John A. Williams ◽  
Georgios V. Gkoutos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Rna Polymerase ◽  
Chromatin Structure ◽  
Drug Targets ◽  
Genetic Alterations ◽  
Specific Gene ◽  
Molecular Dissection ◽  
Cell Identity ◽  
Lineage Specific Gene

Gene expression programmes driving cell identity are established by tightly regulated transcription factors that auto- and cross-regulate in a feed-forward manner, forming core regulatory circuitries (CRCs). CRC transcription factors create and engage super-enhancers by recruiting acetylation writers depositing permissive H3K27ac chromatin marks. These super-enhancers are largely associated with BET proteins, including BRD4, that influence higher-order chromatin structure. The orchestration of these events triggers accessibility of RNA polymerase machinery and the imposition of lineage-specific gene expression. In cancers, CRCs drive cell identity by superimposing developmental programmes on a background of genetic alterations. Further, the establishment and maintenance of oncogenic states are reliant on CRCs that drive factors involved in tumour development. Hence, the molecular dissection of CRC components driving cell identity and cancer state can contribute to elucidating mechanisms of diversion from pre-determined developmental programmes and highlight cancer dependencies. These insights can provide valuable opportunities for identifying and re-purposing drug targets. In this article, we review the current understanding of CRCs across solid and liquid malignancies and avenues of investigation for drug development efforts. We also review techniques used to understand CRCs and elaborate the indication of discussed CRC transcription factors in the wider context of cancer CRC models.

scholarly journals Single nuclei chromatin profiles of ventral midbrain reveal cell identity transcription factors and cell type-specific gene regulatory variation

2020 ◽  
Author(s):  
Yujuan Gui ◽  
Kamil Grzyb ◽  
Mélanie H. Thomas ◽  
Jochen Ohnmacht ◽  
Pierre Garcia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cell Types ◽  
Mouse Strains ◽  
Specific Gene ◽  
Cell Type ◽  
Cell Identity ◽  
Regulatory Variation ◽  
Ventral Midbrain ◽  
Cell Type Specific

SUMMARYCell types in ventral midbrain are involved in diseases with variable genetic susceptibility such as Parkinson’s disease and schizophrenia. Many genetic variants affect regulatory regions and alter gene expression. We report 20 658 single nuclei chromatin accessibility profiles of ventral midbrain from two genetically and phenotypically distinct mouse strains. We distinguish ten cell types based on chromatin profiles and analysis of accessible regions controlling cell identity genes highlights cell type-specific key transcription factors. Regulatory variation segregating the mouse strains manifests more on transcriptome than chromatin level. However, cell type-level data reveals changes not captured at tissue level. To discover the scope and cell-type specificity of cis-acting variation in midbrain gene expression, we identify putative regulatory variants and show them to be enriched at differentially expressed loci. Finally, we find TCF7L2 to mediate trans-acting variation selectively in midbrain neurons. Our dataset provides an extensive resource to study gene regulation in mesencephalon.

Transcription Factors Controlling Muscle-Specific Gene Expression

1993 ◽  
pp. 93-115 ◽  
Author(s):  
John J. Schwarz ◽  
James F. Martin ◽  
Eric N. Olson
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Specific Gene ◽  
Specific Gene Expression

scholarly journals Dynamic changes in cis-regulatory occupancy by Six1 and its cooperative interactions with distinct cofactors drive lineage-specific gene expression programs during progressive differentiation of the auditory sensory epithelium

2020 ◽  
Vol 48 (6) ◽  
pp. 2880-2896 ◽  
Author(s):  
Jun Li ◽  
Ting Zhang ◽  
Aarthi Ramakrishnan ◽  
Bernd Fritzsch ◽  
Jinshu Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
Sensory Epithelium ◽  
Hair Bundle ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Gene Expression ◽  
Wide Range ◽  
Cell Type Specific ◽  
Lineage Specific Gene

Abstract The transcription factor Six1 is essential for induction of sensory cell fate and formation of auditory sensory epithelium, but how it activates gene expression programs to generate distinct cell-types remains unknown. Here, we perform genome-wide characterization of Six1 binding at different stages of auditory sensory epithelium development and find that Six1-binding to cis-regulatory elements changes dramatically at cell-state transitions. Intriguingly, Six1 pre-occupies enhancers of cell-type-specific regulators and effectors before their expression. We demonstrate in-vivo cell-type-specific activity of Six1-bound novel enhancers of Pbx1, Fgf8, Dusp6, Vangl2, the hair-cell master regulator Atoh1 and a cascade of Atoh1’s downstream factors, including Pou4f3 and Gfi1. A subset of Six1-bound sites carry consensus-sequences for its downstream factors, including Atoh1, Gfi1, Pou4f3, Gata3 and Pbx1, all of which physically interact with Six1. Motif analysis identifies RFX/X-box as one of the most significantly enriched motifs in Six1-bound sites, and we demonstrate that Six1-RFX proteins cooperatively regulate gene expression through binding to SIX:RFX-motifs. Six1 targets a wide range of hair-bundle regulators and late Six1 deletion disrupts hair-bundle polarity. This study provides a mechanistic understanding of how Six1 cooperates with distinct cofactors in feedforward loops to control lineage-specific gene expression programs during progressive differentiation of the auditory sensory epithelium.

scholarly journals Specific Secondary Genetic Alterations in Mantle Cell Lymphoma Provide Prognostic Information Independent of the Gene Expression–Based Proliferation Signature

2007 ◽  
Vol 25 (10) ◽  
pp. 1216-1222 ◽  
Author(s):  
Itziar Salaverria ◽  
Andreas Zettl ◽  
Sílvia Beà ◽  
Victor Moreno ◽  
Joan Valls ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cyclin D1 ◽  
Expression Profiles ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Survival Prediction ◽  
Specific Gene ◽  
Prognostic Information ◽  
Substantial Impact ◽  
Mantle Cell

Purpose To compare the genetic relationship between cyclin D1–positive and cyclin D1–negative mantle cell lymphomas (MCLs) and to determine whether specific genetic alterations may add prognostic information to survival prediction based on the proliferation signature of MCLs. Patients and Methods Seventy-one cyclin D1–positive and six cyclin D1–negative MCLs previously characterized by gene expression profiling were examined by comparative genomic hybridization (CGH). Results Cyclin D1–negative MCLs were genetically characterized by gains of 3q, 8q, and 15q, and losses of 1p, 8p23-pter, 9p21-pter, 11q21-q23, and 13q that were also the most common alterations in conventional MCLs. Parallel analysis of CGH aberrations and locus-specific gene expression profiles in cyclin D1–positive patients showed that chromosomal imbalances had a substantial impact on the expression levels of the genes located in the altered regions. The analysis of prognostic factors revealed that the proliferation signature, the number of chromosomal aberrations, gains of 3q, and losses of 8p, 9p, and 9q predicted survival of MCL patients. A multivariate analysis showed that the gene expression-based proliferation signature was the strongest predictor for shorter survival. However, 3q gains and 9q losses provided prognostic information that was independent of the proliferative activity. Conclusion Cyclin D1–positive and –negative MCLs share the same secondary genetic aberrations, supporting the concept that they correspond to the same genetic entity. The integration of genetic information on chromosome 3q and 9q alterations into a proliferation signature-based model may improve the ability to predict survival in patients with MCL.

Dynamics of Genomic Organization.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-17-SCI-17
Author(s):  
Mark T. Groudine ◽  
Indika Rajapakse ◽  
David Scalzo ◽  
Michael Perlman ◽  
Charles L. Kooperberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Time Course ◽  
Genomic Organization ◽  
Conflicts Of Interest ◽  
Cell Types ◽  
Specific Gene ◽  
Chromosomal Association ◽  
Regulated Gene Expression ◽  
Lineage Specific Gene ◽  
Ordered State

Abstract Abstract SCI-17 We have investigated the relationships between lineage-specific gene expression, and total genomic organization during hematopoiesis. First, we determined the linear chromosomal distribution of genes that are co-regulated (identified via microarray analysis) when murine hematopoietic progenitor cells (FDCP-mixA) are differentiated to the erythroid and neutrophil lineages, as well as the organization of all chromosomes (in the form of rosettes) in the three cell types. Our analysis revealed a significant tendency for co-regulated genes to be proximal, which is related to the association of homologous chromosomes and the spatial juxtaposition of lineage-specific gene domains. This led us to hypothesize that the genome—at the level of chromosomes—may self-organize to facilitate coordinate gene regulation during cellular differentiation. We tested this hypothesis by applying the approaches of distance matrices and coupled oscillators to our datasets of gene expression and chromosomal associations from the differentiation of the progenitor to the erythroid and neutrophil lineages. Our analysis revealed that coordinate gene expression undergoes a phase transition—characterized by an increase in entropy—upon commitment of the progenitor. As differentiation continues, there is a gradual loss of entropy, culminating in a highly ordered state in the differentiated cell types. The coregulated gene sets of the semi-ordered progenitor and ordered erythroid and neutrophil lineages are significantly correlated with lineage-specific chromosomal association patterns. Furthermore, by transforming the gene expression networks along the time course to corresponding chromosomal association matrices, we found that chromosomal topologies change dynamically during differentiation but, as with gene expression, result in a more highly ordered state in the differentiated cell types. Our analysis demonstrates that the networks of co-regulated gene expression and chromosomal association are mutually related during differentiation, resulting in the self-organization of lineage-specific chromosomal topologies. Disclosures No relevant conflicts of interest to declare.

scholarly journals The GATA-4 transcription factor transactivates the cardiac muscle-specific troponin C promoter-enhancer in nonmuscle cells.

1994 ◽  
Vol 14 (11) ◽  
pp. 7517-7526 ◽  
Author(s):  
H S Ip ◽  
D B Wilson ◽  
M Heikinheimo ◽  
Z Tang ◽  
C N Ting ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Cardiac Muscle ◽  
Binding Site ◽  
Cardiac Myocytes ◽  
Specific Binding ◽  
Troponin C ◽  
Specific Gene ◽  
Cardiac Muscle Cells

The unique contractile phenotype of cardiac myocytes is determined by the expression of a set of cardiac muscle-specific genes. By analogy to other mammalian developmental systems, it is likely that the coordinate expression of cardiac genes is controlled by lineage-specific transcription factors that interact with promoter and enhancer elements in the transcriptional regulatory regions of these genes. Although previous reports have identified several cardiac muscle-specific transcriptional elements, relatively little is known about the lineage-specific transcription factors that regulate these elements. In this report, we demonstrate that the slow/cardiac muscle-specific troponin C (cTnC) enhancer contains a specific binding site for the lineage-restricted zinc finger transcription factor GATA-4. This GATA-4-binding site is required for enhancer activity in primary cardiac myocytes. Moreover, the cTnC enhancer can be transactivated by overexpression of GATA-4 in non-cardiac muscle cells such as NIH 3T3 cells. In situ hybridization studies demonstrate that GATA-4 and cTnC have overlapping patterns of expression in the hearts of postimplantation mouse embryos and that GATA-4 gene expression precedes cTnC expression. Indirect immunofluorescence reveals GATA-4 expression in cultured cardiac myocytes from neonatal rats. Taken together, these results are consistent with a model in which GATA-4 functions to direct tissue-specific gene expression during mammalian cardiac development.

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