scholarly journals BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dominik Laubscher ◽  
Berkley E. Gryder ◽  
Benjamin D. Sunkel ◽  
Thorkell Andresson ◽  
Marco Wachtel ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Target Genes ◽  
De Novo ◽  
Fusion Gene ◽  
Myogenic Differentiation ◽  
Complex Function ◽  
Genome Wide ◽  
Myogenic Program

AbstractRhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters the myogenic program and maintains the proliferative state while blocking terminal differentiation. Here, we investigated the contributions of chromatin regulatory complexes to FP-RMS tumor maintenance. We define the mSWI/SNF functional repertoire in FP-RMS. We find that SMARCA4 (encoding BRG1) is overexpressed in this malignancy compared to skeletal muscle and is essential for cell proliferation. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which is further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with core regulatory transcription factors. Further, mSWI/SNF complexes localize to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes, which is recapitulated by BRG1 targeting compounds. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for this lethal childhood tumor.

scholarly journals BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma

2021 ◽  
Author(s):  
Dominik Laubscher ◽  
Berkley Gryder ◽  
Benjamin Sunkel ◽  
Thorkell Andresson ◽  
Sudipto Das ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Target Genes ◽  
De Novo ◽  
Fusion Gene ◽  
Myogenic Differentiation ◽  
Complex Function ◽  
Genome Wide ◽  
Myogenic Program

Abstract Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters the myogenic program and maintains the proliferative state wile blocking terminal differentiation. Here we investigated the contributions of chromatin regulatory complexes to FP-RMS tumor maintenance. We define, for the first time, the mSWI/SNF repertoire in FP-RMS. We find that SMARCA4 (encoding BRG1) is overexpressed in this malignancy compared to skeletal muscle and is essential for cell proliferation. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which is further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with core regulatory transcription factors. Further, mSWI/SNF complexes act as sensors of chromatin state and are recruited to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes which is reproduced by BRG1 targeting compounds. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for this lethal childhood tumor.

Myocyte nuclear factor, a novel winged-helix transcription factor under both developmental and neural regulation in striated myocytes

1994 ◽  
Vol 14 (7) ◽  
pp. 4596-4605
Author(s):  
R Bassel-Duby ◽  
M D Hernandez ◽  
Q Yang ◽  
J M Rochelle ◽  
M F Seldin ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activation ◽  
Myogenic Differentiation ◽  
Specific Binding ◽  
Motor Nerve ◽  
Sequence Motif ◽  
Nuclear Factor ◽  
Winged Helix ◽  
Amino Terminal ◽  
Myocyte Nuclear Factor

A sequence motif (CCAC box) within an upstream enhancer region of the human myoglobin gene is essential for transcriptional activity in both cardiac and skeletal muscle. A cDNA clone, myocyte nuclear factor (MNF), was isolated from a murine expression library on the basis of sequence-specific binding to the myoglobin CCAC box motif and was found to encode a novel member of the winged-helix or HNF-3/fork head family of transcription factors. Probes based on this sequence identify two mRNA species that are upregulated during myocyte differentiation, and antibodies raised against recombinant MNF identify proteins of approximately 90, 68, and 65 kDa whose expression is regulated following differentiation of myogenic cells in culture. In addition, the 90-kDa form of MNF is phosphorylated and is upregulated in intact muscles subjected to chronic motor nerve stimulation, a potent stimulus to myoglobin gene regulation. Amino acid residues 280 to 389 of MNF demonstrate 35 to 89% sequence identity to the winged-helix domain from other known members of this family, but MNF is otherwise divergent. A proline-rich amino-terminal region (residues 1 to 206) of MNF functions as a transcriptional activation domain. These studies provide the first evidence that members of the winged-helix family of transcription factors have a role in myogenic differentiation and in remodeling processes of adult muscles that occur in response to physiological stimuli.

Genome-Wide Analysis Reveals PADI4 Facilitates Transcriptional Activation of a Subset of Elk-1 Target Genes in MCF-7 Cells.

2010 ◽  
pp. P1-108-P1-108
Author(s):  
XS Zhang ◽  
MJ Gamble ◽  
S Stadler ◽  
BD Cherrington ◽  
MS Roberson ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Mcf 7

scholarly journals BICORN: An R package for integrative inference of de novo cis-regulatory modules

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Xi Chen ◽  
Jinghua Gu ◽  
Andrew F. Neuwald ◽  
Leena Hilakivi-Clarke ◽  
Robert Clarke ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Target Genes ◽  
De Novo ◽  
R Package ◽  
Model Parameters ◽  
Expression Data ◽  
Regulatory Modules ◽  
Genome Wide ◽  
Context Specific ◽  
Tf Gene

Abstract Genome-wide transcription factor (TF) binding signal analyses reveal co-localization of TF binding sites, based on which cis-regulatory modules (CRMs) can be inferred. CRMs play a key role in understanding the cooperation of multiple TFs under specific conditions. However, the functions of CRMs and their effects on nearby gene transcription are highly dynamic and context-specific and therefore are challenging to characterize. BICORN (Bayesian Inference of COoperative Regulatory Network) builds a hierarchical Bayesian model and infers context-specific CRMs based on TF-gene binding events and gene expression data for a particular cell type. BICORN automatically searches for a list of candidate CRMs based on the input TF bindings at regulatory regions associated with genes of interest. Applying Gibbs sampling, BICORN iteratively estimates model parameters of CRMs, TF activities, and corresponding regulation on gene transcription, which it models as a sparse network of functional CRMs regulating target genes. The BICORN package is implemented in R (version 3.4 or later) and is publicly available on the CRAN server at https://cran.r-project.org/web/packages/BICORN/index.html.

scholarly journals Central clock components modulate plant shade avoidance by directly repressing transcriptional activation activity of PIF proteins

2020 ◽  
Vol 117 (6) ◽  
pp. 3261-3269 ◽  
Author(s):  
Yu Zhang ◽  
Anne Pfeiffer ◽  
James M. Tepperman ◽  
Jutta Dalton-Roesler ◽  
Pablo Leivar ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Direct Action ◽  
Published Data ◽  
Shade Avoidance ◽  
Response Regulators ◽  
Genome Wide ◽  
Promoter Occupancy ◽  
Factor Abundance ◽  
Direct Target

Light-environment signals, sensed by plant phytochrome photoreceptors, are transduced to target genes through direct regulation of PHYTOCHROME-INTERACTING FACTOR (PIF) transcription factor abundance and activity. Previous genome-wide DNA-binding and expression analysis has identified a set of genes that are direct targets of PIF transcriptional regulation. However, quantitative analysis of promoter occupancy versus expression level has suggested that unknown “trans factors” modulate the intrinsic transcriptional activation activity of DNA-bound PIF proteins. Here, using computational analysis of published data, we have identified PSEUDO-RESPONSE REGULATORS (PRR5 and PRR7) as displaying a high frequency of colocalization with the PIF proteins at their binding sites in the promoters of PIF Direct Target Genes (DTGs). We show that the PRRs function to suppress PIF-stimulated growth in the light and vegetative shade and that they repress the rapid PIF-induced expression of PIF-DTGs triggered by exposure to shade. The repressive action of the PRRs on both growth and DTG expression requires the PIFs, indicating direct action on PIF activity, rather than a parallel antagonistic pathway. Protein interaction assays indicate that the PRRs exert their repressive activity by binding directly to the PIF proteins in the nucleus. These findings support the conclusion that the PRRs function as direct outputs from the core circadian oscillator to regulate the expression of PIF-DTGs through modulation of PIF transcriptional activation activity, thus expanding the roles of the multifunctional PIF-signaling hub.

scholarly journals hMEF2C gene encodes skeletal muscle- and brain-specific transcription factors.

1993 ◽  
Vol 13 (4) ◽  
pp. 2564-2577 ◽  
Author(s):  
J C McDermott ◽  
M C Cardoso ◽  
Y T Yu ◽  
V Andres ◽  
D Leifer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factors ◽  
Cortical Neurons ◽  
Myogenic Differentiation ◽  
Mrna Level ◽  
Functional Characterization ◽  
Essential Element ◽  
Specific Pattern ◽  
Cdna Clones ◽  
Tissue Specific

The myocyte enhancer-binding factor 2 (MEF2) site is an essential element of many muscle-specific enhancers and promoters that binds nuclear proteins from muscle and brain. Recently, we have cloned a family of MEF2 transcription factors produced by two genes that, at the mRNA level, are broadly expressed and produce tissue-specific isoforms by posttranscriptional processes (Y.-T. Yu, R. E. Breitbart, L. B. Smoot, Y. Lee, V. Mahdavi, and B. Nadal-Ginard, Genes Dev. 6:1783-1798, 1992). Here, we report the isolation and functional characterization of cDNA clones encoding four MEF2 factors derived from a separate gene that we have named hMEF2C. In contrast to those of the previously reported genes, the transcripts of the hMEF2C gene are restricted to skeletal muscle and brain. One of the alternate exons is exclusively present in brain transcripts. The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors. The hMEF2C gene is induced late during myogenic differentiation, and its expression is limited to a subset of cortical neurons. The potential targets for this transcription factor in a subset of neurons are not known at this time. The strict tissue-specific pattern of expression of hMEF2C in comparison with the more ubiquitous expression of other MEF2 genes suggests a different mode of regulation and a potentially important role of hMEF2C factors in myogenesis and neurogenesis.

scholarly journals Histone deacetylase 3 preferentially binds and collaborates with the transcription factor RUNX1 to repress AML1–ETO–dependent transcription in t(8;21) AML

2020 ◽  
Vol 295 (13) ◽  
pp. 4212-4223 ◽  
Author(s):  
Chun Guo ◽  
Jian Li ◽  
Nickolas Steinauer ◽  
Madeline Wong ◽  
Brent Wu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fusion Protein ◽  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Chromosomal Translocation ◽  
Histone Deacetylase 3 ◽  
Genome Wide ◽  
Related Transcription Factor ◽  
Almost All

In up to 15% of acute myeloid leukemias (AMLs), a recurring chromosomal translocation, termed t(8;21), generates the AML1–eight–twenty-one (ETO) leukemia fusion protein, which contains the DNA-binding domain of Runt-related transcription factor 1 (RUNX1) and almost all of ETO. RUNX1 and the AML1–ETO fusion protein are coexpressed in t(8;21) AML cells and antagonize each other's gene-regulatory functions. AML1–ETO represses transcription of RUNX1 target genes by competitively displacing RUNX1 and recruiting corepressors such as histone deacetylase 3 (HDAC3). Recent studies have shown that AML1–ETO and RUNX1 co-occupy the binding sites of AML1–ETO–activated genes. How this joined binding allows RUNX1 to antagonize AML1–ETO–mediated transcriptional activation is unclear. Here we show that RUNX1 functions as a bona fide repressor of transcription activated by AML1–ETO. Mechanistically, we show that RUNX1 is a component of the HDAC3 corepressor complex and that HDAC3 preferentially binds to RUNX1 rather than to AML1–ETO in t(8;21) AML cells. Studying the regulation of interleukin-8 (IL8), a newly identified AML1–ETO–activated gene, we demonstrate that RUNX1 and HDAC3 collaboratively repress AML1–ETO–dependent transcription, a finding further supported by results of genome-wide analyses of AML1–ETO–activated genes. These and other results from the genome-wide studies also have important implications for the mechanistic understanding of gene-specific coactivator and corepressor functions across the AML1–ETO/RUNX1 cistrome.

scholarly journals Cell transformation mediated by homodimeric E2A-HLF transcription factors.

1997 ◽  
Vol 17 (3) ◽  
pp. 1417-1424 ◽  
Author(s):  
T Inukai ◽  
T Inaba ◽  
T Yoshihara ◽  
A T Look
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Fusion Gene ◽  
Dominant Negative ◽  
Fusion Product ◽  
3T3 Cells ◽  
Par Proteins ◽  
Downstream Target ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

The E2A-HLF fusion gene, created by the t(17;19)(q22;p13) chromosomal translocation in pro-B lymphocytes, encodes an oncogenic protein in which the E2A trans-activation domain is linked to the DNA-binding and protein dimerization domain of hepatic leukemia factor (HLF), a member of the proline- and acidic amino acid-rich (PAR) subfamily of bZIP transcription factors. This fusion product binds to its DNA recognition site not only as a homodimer but also as a heterodimer with HLF and two other members of the PAR bZIP subfamily, thyrotroph embryonic factor (TEF) and albumin promoter D-box binding protein (DBP). Thus, E2A-HLF could transform cells by direct regulation of downstream target genes, acting through homodimeric or heterodimeric complexes, or by sequestering normal PAR proteins into nonfunctional heterocomplexes (dominant-negative interference). To distinguish among these models, we constructed mutant E2A-HLF proteins in which the leucine zipper domain of HLF was extended by one helical turn or altered in critical charged amino acids, enabling the chimera to bind to DNA as a homodimer but not as a heterodimer with HLF or other PAR proteins. When introduced into NIH 3T3 cells in a zinc-inducible vector, each of these mutants induced anchorage-independent growth as efficiently as unaltered E2A-HLF, indicating that the chimeric oncoprotein can transform cells in its homodimeric form. Transformation also depended on an intact E2A activator region, providing further support for a gain-of-function contribution to oncogenesis rather than one based on a dominant-interfering or dominant-negative mechanism. Thus, the tumorigenic effects of E2A-HLF and its mutant forms in NIH 3T3 cells favor a straightforward model in which E2A-HLF homodimers bind directly to promoter/enhancer elements of downstream target genes and alter their patterns of expression in early B-cell progenitors.

scholarly journals A New Role for Sterol Regulatory Element Binding Protein 1 Transcription Factors in the Regulation of Muscle Mass and Muscle Cell Differentiation

2009 ◽  
Vol 30 (5) ◽  
pp. 1182-1198 ◽  
Author(s):  
Virginie Lecomte ◽  
Emmanuelle Meugnier ◽  
Vanessa Euthine ◽  
Christine Durand ◽  
Damien Freyssenet ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Muscle Mass ◽  
Target Genes ◽  
Binding Protein ◽  
Regulatory Element ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Myogenic Program

ABSTRACT The role of the transcription factors sterol regulatory element binding protein 1a (SREBP-1a) and SREBP-1c in the regulation of cholesterol and fatty acid metabolism has been well studied; however, little is known about their specific function in muscle. In the present study, analysis of recent microarray data from muscle cells overexpressing SREBP1 suggested that they may play a role in the regulation of myogenesis. We then demonstrated that SREBP-1a and -1c inhibit myoblast-to-myotube differentiation and also induce in vivo and in vitro muscle atrophy. Furthermore, we have identified the transcriptional repressors BHLHB2 and BHLHB3 as mediators of these effects of SREBP-1a and -1c in muscle. Both repressors are SREBP-1 target genes, and they affect the expression of numerous genes involved in the myogenic program. Our findings identify a new role for SREBP-1 transcription factors in muscle, thus linking the control of muscle mass to metabolic pathways.

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